JPH09323983A - Oxazole derivative, its production and medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new oxazole derivative having an excellent insulin secretion-stimulating action and an excellent hypoglycemic action, useful as a diabetes-treating medicine and low in toxicity. SOLUTION: This compound is represented by formula I (R<1> is a halogen, a heterocyclic group, hydroxy, thiol, etc.; A is an acyl, a heterocyclic group, hydroxy, carboxy which may be esterified or amidated; B is an aromatic group; Y is a divalent aliphatic hydrocarbon) or its salt, e.g. 4-(4-chlorophenyl)-2-(2- methyl-1-imidazolyl)-5-oxazole propanol or its salt. The compound of formula I is obtained e.g. by reacting a compound of formula II or its salt with a halogenating agent. Thereby, good insulin secretion-stimulating medicines, diabetes-preventing and treating medicines, antihypertensive agents, etc., can be obtained from the compound of formula I.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel oxazole derivative useful as a therapeutic agent for diabetes, a method for producing the same, and an agent.

[0002]

2. Description of the Related Art Conventionally, various biguanide compounds and sulfonylurea compounds have been used as therapeutic agents for diabetes. However, since biguanide compounds cause lactic acidosis, they are rarely used at present.Although sulfonylurea compounds have a strong hypoglycemic effect, they often cause severe hypoglycemia and require caution in use. is there. Further, oxazole derivatives having a blood glucose lowering action and a glucose tolerance improving action are disclosed in JP-A-58-183676 and JP-A-59-19097.
9, JP-A-2-289556.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel compound having excellent insulin secretion promoting action and hypoglycemic action, useful as a therapeutic agent for diabetes and having low toxicity. .

[0004]

Means for Solving the Problems The present inventors have conducted various studies on oxazole derivatives, and as a result, the novel derivative represented by the following general formula (I) has an excellent hypoglycemic action and / or insulin secretagogue action. The present invention has been completed and the present invention has been completed. That is, the present invention has the general formula

[Chemical 7] [In the formula, R ¹ represents a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, and A is B may be substituted with an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified or amidated carboxy group. An aromatic group, Y represents a divalent aliphatic hydrocarbon group] or a salt thereof, and a compound represented by the general formula (I) (oxazole derivative) or a pharmaceutically acceptable salt thereof. The present invention provides a pharmaceutical composition containing a possible salt as an active ingredient.

In the general formula (I), the heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ or A includes, as ring-constituting atoms, a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms. Examples thereof include a 5- or 6-membered ring containing 1 to 4 selected atoms or a condensed ring thereof. Examples of the condensed ring include such a 5- or 6-membered ring and 1
Alternatively, a 6-membered ring containing two nitrogen atoms, a benzene ring or a condensed ring with a 5-membered ring containing one sulfur atom may be mentioned.
Specific examples of the heterocyclic group include, for example, pyridyl (eg, 2-
Pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrimidinyl (eg, 2-pyrimidinyl, 5-pyrimidinyl, 6-
Pyrimidinyl, etc.), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl, etc.), pyrazinyl (eg, 2-pyrazinyl, etc.), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, etc.), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, etc.), isoxazolyl, isothiazolyl, thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5- Thiazolyl etc.), oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl etc.), 1,2,4-oxadiazolyl (eg 1,2,4-
Oxadiazol-5-yl, etc.), 1,2,4-triazolyl (eg, 1,2,4-triazol-1-yl, 1,
2,4-triazol-3-yl, etc.), 1,2,3-triazolyl (eg, 1,2,3-triazol-2-yl,
1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl, etc.), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl) Etc.), indolyl (eg, indol-1-yl, indol-3-
1H-indazolyl (eg, 1H-indazol-1-yl, etc.), 1H-pyrrolo [2,3-b] pyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazine-1-
1H-pyrrolo [2,3-b] pyridyl (eg,
1H-pyrrolo [2,3-b] pyridin-1-yl etc.),
1H-imidazo [4,5-b] pyridyl (eg, 1H-imidazo [4,5-b] pyridin-1-yl etc.), 1H-
Imidazo [4,5-c] pyridyl (eg, 1H-imidazo [4,5-c] pyridin-1-yl, etc.), 1H-imidazo [4,5-b] pyrazinyl (eg, 1H-imidazo [4,
5-b] pyrazin-1-yl etc.) and an aromatic heterocyclic group; and pyrrolidinyl (eg 1-pyrrolidinyl etc.),
Piperidinyl (eg, piperidino etc.), morpholinyl (eg, morpholino etc.), piperazinyl (eg, 1-piperazinyl etc.), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl etc.), oxazolidinyl (eg, oxazolidine-3) -Yl etc.), thiazolidinyl (eg, thiazolidin-3-yl, thiazolidin-2-yl etc.),
Imidazolidinyl (eg, imidazolidin-3-yl etc.), imidazolinyl (eg, imidazolin-1-yl,
Imidazolin-2-yl etc.), oxazolinyl (eg oxazolin-2-yl etc.), thiazolinyl (eg thiazolin-2-yl etc.), oxazinyl (eg oxazine-
Non-aromatic heterocyclic group such as 2-yl) and the like, and preferably, for example, an azolyl group (eg, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1 , 2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl and the like), azolinyl group (for example, imidazolinyl, oxazolinyl, thiazolinyl and the like), azolidinyl group (for example, pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl and the like).

The heterocyclic group represented by R ¹ or A may have 1 to 3 substituents at substitutable positions. Examples of the substituent include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and an optionally substituted amino group. , An optionally substituted acyl group, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally esterified or amidated carboxy group, and an oxo group. Examples of the heterocyclic group substituted with an oxo group include an azolidinyl group substituted with 1 or 2 oxo groups, and specific examples thereof include 2-oxoimidazolidinyl (for example, 2-oxo group). Imidazolidin-1-yl etc.),
2,4-dioxoimidazolidinyl (eg, 2,4-
Dioxoimidazolidin-3-yl etc.), 2,4-dioxooxazolidinyl (eg 2,4-dioxooxazolidin-3-yl etc.) or 2,4-dioxothiazolidinyl (eg , 2,4-dioxothiazolidine-
3-yl etc.) and the like.

The aliphatic hydrocarbon group has 1 to 1 carbon atoms.
The linear or branched aliphatic hydrocarbon group of 5, for example, an alkyl group, an alkenyl group, an alkynyl group and the like can be mentioned. Preferable examples of the alkyl group include alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-. Pentyl, 1-ethylpropyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,
3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl and the like.
Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, such as vinyl, allyl, isopropenyl,
1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1
-Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2
-Hexenyl, 3-hexenyl, 4-hexenyl, 5-
Hexenyl and the like. Preferable examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2
-Pentynyl, 3-pentynyl, 4-pentynyl, 1-
Hexinyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like can be mentioned.

The alicyclic hydrocarbon group has 3 to 1 carbon atoms.
And 2 saturated or unsaturated alicyclic hydrocarbon groups such as cycloalkyl groups, cycloalkenyl groups, and cycloalkadienyl groups. Preferable examples of the cycloalkyl group include cycloalkyl groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2. 2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.
2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and the like. As a preferable example of the cycloalkenyl group, a cycloalkenyl group having 3 to 10 carbon atoms, for example, 2-
Cyclopenten-1-yl, 3-cyclopenten-1-
And 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. A preferred example of the cycloalkadienyl group is a cycloalkadienyl group having 4 to 10 carbon atoms, such as 2,4-cyclopentadiene-1.
-Yl, 2,4-cyclohexadiene-1-yl, 2,5
-Cyclohexadien-1-yl and the like. The aryl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group, and preferable examples thereof include aryl groups having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

Preferable examples of the aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
Aromatic monocyclic heterocyclic groups such as triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,
2-benzisoxazolyl, benzothiazolyl, 1,
2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, Phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrollinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-
a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,
2,4-triazolo [4,3-a] pyridyl, 1,2,4-
And aromatic condensed heterocyclic groups such as triazolo [4,3-b] pyridazinyl.

Preferable examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl and the like. Examples of the halogen atom include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable. Examples of the optionally substituted amino group include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, and 1 carbon atom.
Mono- or di-substituted with an acyl group having 10 to 10 (eg, formyl, C _1-9 alkyl-carbonyl, etc.) or an aromatic group having 6 to 12 carbon atoms (eg, C _6-12 aryl such as phenyl), etc. And an amino group (—NH ₂ group) which may be mentioned. Examples of the substituted amino group include methylamino, dimethylamino, ethylamino, diethylamino,
Examples thereof include dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino and N-methyl-N-phenylamino.

As the acyl group in the optionally substituted acyl group, an acyl group having 1 to 13 carbon atoms, specifically, formyl, for example, an alkyl group having 1 to 10 carbon atoms,
Cycloalkyl group having 3 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbon atoms or aromatic group having 6 to 12 carbon atoms (eg, C _6-12 aryl group such as phenyl) Etc.) and a carbonyl group bonded to each other (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, etc., C _1-10 alkyl-carbonyl group; cyclobutanecarbonyl, cyclopentanecarbonyl, C _3-10 cycloalkenyl such as 2-cyclohexene-carbonyl - carbonyl group; carbonyl group - C _2-10 alkenyl such as crotonyl; carbonyl group - cyclohexanecarbonyl, C _3-10 cycloalkyl, such as cycloheptane carbonyl benzoyl, nicotinoyl, etc. C _6-12 Allee Carbonyl group). Examples of the substituent in the substituted acyl group include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, halogen (eg, chlorine, fluorine, bromine, etc.), nitro, hydroxy, amino and the like. To be

In the optionally substituted hydroxy group, examples of the substituted hydroxy group include an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group, an alkylsulfonyloxy group and an arylsulfonyloxy group. Is mentioned.
Preferable examples of the alkoxy group include alkoxy groups having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy,
Examples thereof include isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Preferable examples of the alkenyloxy group include alkenyloxy groups having 2 to 10 carbon atoms, such as allyloxy,
Examples include crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like. Preferable examples of the aralkyloxy group include an aralkyloxy group having a carbon number of 7 to 10, such as a phenyl-C _1-4 alkyloxy group (eg, benzyloxy, phenethyloxy, etc.) and the like. Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, more preferably 2 carbon atoms.
To alkanoyloxy groups (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) and the like. Preferable examples of the aryloxy group include C6 to C14.
Aryloxy groups such as phenoxy and naphthyloxy. The aryloxy group is 1 to 2
It may have one substituent, and examples of such a substituent include halogen (eg, chlorine, fluorine, bromine, etc.), alkoxy having 1 to 4 carbon atoms, and the like. Examples of the substituted aryloxy group include 4-chlorophenoxy and 2-methoxyphenoxy. Preferable examples of the alkylsulfonyloxy group include an alkylsulfonyloxy group having 1 to 10 carbon atoms, such as methylsulfonyloxy and ethylsulfonyloxy. Preferable examples of the arylsulfonyloxy group include an arylsulfonyloxy group having 6 to 12 carbon atoms (the C _6-12 arylsulfonyloxy group is C such as methyl).
_1-6 alkyl may be substituted), for example, phenylsulfonyloxy, 4-methylphenylsulfonyloxy and the like.

In the optionally substituted thiol group (optionally substituted mercapto group), examples of the substituted thiol group include alkylthio group, arylthio group, heteroarylthio group, aralkylthio group and heteroarylalkylthio group. Group, acylthio group and the like. Preferable examples of the alkylthio group include 1 to 1 carbon atoms.
10 alkylthio groups (eg, methylthio, ethylthio,
Propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. To be A preferred example of the arylthio group is C
_1-6 carbon atoms optionally substituted with an alkyl group 6-14
Arylthio groups such as phenylthio, naphthylthio, and 4-methylphenylthio. Examples of the heteroarylthio group include a thiol group substituted with the above-mentioned aromatic heterocyclic group, and among them, 2-
Pyridylthio, 3-pyridylthio, 2-imidazolylthio, 1,2,4-triazol-5-ylthio and the like are preferable. Preferable examples of the aralkylthio group include 7 to 7 carbon atoms.
10 aralkylthio groups, such as phenyl-C _1-4 alkylthio groups (eg, benzylthio, phenethylthio, etc.)
And the like. Examples of the heteroarylalkylthio group include an alkylthio group substituted with the aromatic heterocyclic group described above. Here, the alkylthio group may be the same as the above-mentioned alkylthio group.
Preferable examples of the heteroarylalkylthio group include a pyridyl-C _1-4 alkylthio group (eg, 2-pyridylmethylthio, 3-pyridylmethylthio, etc.) and the like.
Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanoylthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) and the like.

In the carboxy group which may be esterified or amidated, examples of the esterified carboxy group include an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group and a heteroarylalkyloxycarbonyl group. To be Preferable examples of the alkoxycarbonyl group include an alkoxycarbonyl group having 2 to 5 carbon atoms, for example, a C _1-4 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Preferable examples of the aralkyloxycarbonyl group include an aralkyloxycarbonyl group having 8 to 10 carbon atoms, for example, a C _7-9 aralkyloxy-carbonyl group such as benzyloxycarbonyl. Preferable examples of the aryloxycarbonyl group include an aryloxycarbonyl group having 7 to 15 carbon atoms which may be substituted with a C _1-6 alkyl group, for example, C _6-14 such as phenoxycarbonyl and p-tolyloxycarbonyl. An aryloxy-carbonyl group etc. are mentioned.
As the heteroarylalkyloxycarbonyl group,
For example, an alkyloxycarbonyl group substituted by the above-mentioned aromatic heterocyclic group can be mentioned. Here, the alkyloxycarbonyl group may be the same as the above-mentioned alkoxycarbonyl group. A preferred example of the heteroarylalkyloxycarbonyl group is pyridyl-C.
_1-4 alkoxy-carbonyl group (eg, 2-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl, etc.)
And the like.

In the carboxyl group which may be esterified or amidated, the amidated carboxyl group is represented by the formula: -CON (R ⁵ ) (R ⁶ ) [wherein
R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted heterocyclic group]
And a group represented by. Here, the hydrocarbon group in the optionally substituted hydrocarbon group represented by R ⁵ or R ⁶ is an aliphatic hydrocarbon group or an aliphatic hydrocarbon group exemplified as the substituent of the heterocyclic group represented by R ¹ or A. Examples thereof include cyclic hydrocarbon groups and aryl groups. The optionally substituted hydroxy group represented by R ⁵ or R ⁶ includes
Examples thereof include the same groups as the optionally substituted hydroxy group represented by R ¹ or A. Also, R ⁵ or R ⁶
Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by are the aromatic heterocyclic groups exemplified as the substituent of the heterocyclic group represented by R ¹ or A. The substituent for R ⁵ or R ⁶ includes a halogen atom (eg,
Chlorine, fluorine, bromine. 1 to 3 substituents selected from an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and the like.

In the general formula (I), the substituents on the heterocyclic group represented by R ¹ or A are alicyclic hydrocarbon group, aryl group, aromatic heterocyclic group and non-aromatic heterocyclic group. When it is, each may further have one or more suitable substituents, preferably 1 to 3, and examples of such a substituent include, for example, an alkyl group having 1 to 6 carbon atoms and 2 to 2 carbon atoms. 6 alkenyl group, 2 to 6 carbon alkynyl group, 3 carbon atoms
~ 7 cycloalkyl group, C6-14 aryl group (eg, phenyl, naphthyl, etc.), aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic group (Eg, tetrahydrofuryl, morpholino, piperidino, pyrrolidino, piperazino, etc.), aralkyl group having 7 to 9 carbon atoms (eg, benzyl, etc.), amino group, N-mono (C _1-4 ) alkylamino group, N, N -Di (C _1-4 ) alkylamino group, acylamino group having 2 to 8 carbon atoms (eg, C _1-7 alkyl-carbonylamino such as acetylamino, propionylamino; benzoylamino etc.), amidino group, 2 carbon atoms ~
8 acyl groups (eg, C _1-7 alkyl-carbonyl such as acetyl), carbamoyl groups, N-mono (C _1-4 ).
Alkylcarbamoyl group, N, N-di (C _1-4 ) alkylcarbamoyl group, sulfamoyl group, N-mono (C
_1-4 ) Alkylsulfamoyl group, N, N-di (C _1-4 ).
Alkylsulfamoyl group, carboxyl group, carbon number 2
To alkoxycarbonyl group, hydroxy group, alkoxy group having 1 to 4 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms, cycloalkyloxy group having 3 to 7 carbon atoms, aralkyloxy group having 7 to 9 carbon atoms ( Benzyloxy, etc.), aryloxy groups having 6 to 14 carbon atoms (eg, phenyloxy, naphthyloxy, etc.), mercapto groups, alkylthio groups having 1 to 4 carbon atoms, aralkylthio groups having 7 to 9 carbon atoms (eg, , Benzylthio, etc.), arylthio groups having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio, etc.), sulfo group, cyano group, azido group, nitro group, nitroso group, halogen atom (eg, fluorine, chlorine, bromine, iodine) And so on.

[0017] In the formula (I), the halogen atom represented by R ^1, an optionally substituted hydroxy group, an optionally substituted thiol group, the amino group which may be substituted, R ¹ or What was illustrated as a substituent in the heterocyclic group shown by A is mentioned. General formula (I)
In the above, R ¹ is preferably an optionally substituted heterocyclic group.

In the general formula (I), as the optionally substituted acyl group, optionally substituted hydroxy group, and optionally esterified or amidated carboxy group, R ¹ or What was illustrated as a substituent in the heterocyclic group shown by A is mentioned. In general formula (I), A is preferably an optionally substituted heterocyclic group or an optionally substituted hydroxy group.

In the general formula (I), examples of the aromatic group which may be substituted and is represented by B include an aromatic hydrocarbon group and an aromatic heterocyclic group. Preferable examples of the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms, for example, a C _6-14 aryl group (eg, phenyl, naphthyl) and the like. Preferable examples of the aromatic heterocyclic group include those exemplified as the substituent in the heterocyclic group represented by R ¹ or A, and among them,
For example, furyl, thienyl, pyridyl, quinolyl and the like are preferable. Examples of the substituent in the optionally substituted aromatic group represented by B include a halogen atom, a nitro group,
Examples thereof include 1 to 3 substituents selected from a cyano group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group and the like. Here, examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like. Examples of the alkoxy group in the optionally substituted alkoxy group include those exemplified as the substituents in the heterocyclic group represented by R ¹ or A, and among them, the number of carbon atoms is 1 to 6
The linear or branched alkoxy group of is preferable. Examples of the alkyl group in the optionally substituted alkyl group include those exemplified as the substituents in the heterocyclic group represented by R ¹ or A, and among them, the number of carbon atoms is 1 to 6
The linear or branched alkyl group of is preferred. Examples of the cycloalkyl group in the optionally substituted cycloalkyl group include those exemplified as the substituents in the heterocyclic group represented by R ¹ or A, and above all, a cycloalkyl group having 3 to 7 carbon atoms is a cycloalkyl group. preferable. Examples of the substituent in the above-mentioned optionally substituted alkoxy group, optionally substituted alkyl group and optionally substituted cycloalkyl group include a halogen atom (eg, fluorine, chlorine, bromine, iodine), Hydroxy group,
Examples thereof include 1 to 3 substituents selected from an alkoxy group having 1 to 6 carbon atoms. Examples of the substituted alkoxy group include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1-difluoroethoxy and the like. Examples of the substituted alkyl group include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, 1-hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl and 2,2-dimethoxy. Ethyl etc. are mentioned. In the general formula (I), B is preferably an aromatic hydrocarbon group which may be substituted, and a phenyl group which may be substituted is generally used.

In the general formula (I), the divalent aliphatic hydrocarbon group represented by Y may be linear or branched and may be saturated or unsaturated. The aliphatic hydrocarbon group preferably has 1 to 7 carbon atoms, and specific examples _{-CH 2 -, - CH (CH} 3) -, - (C
_{H 2) 2 -, - CH} (C 2 H 5) -, - (CH 2) 3 -, -
(CH ₂ ) ₄ −, − (CH ₂ ) ₅ −, − (CH ₂ ) ₆ −, −
(CH _{2) 7} - ones like saturated, for example, -CH = CH-,
_{-C (CH 3) = CH -} , - CH = CH-CH 2 -, - C
_{(C 2 H 5) = CH} -, - CH 2 -CH = CH-CH 2 -,
_{-CH 2 -CH 2 -CH = CH-} CH 2 -, - CH = CH
_{-CH = CH-CH 2 -,} - CH = CH-CH = CH-
CH = CH-CH ₂ - include those of the unsaturated and the like.
Y is preferably a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, and more preferably saturated. Preferred examples of Y, for example, - (CH _{2) 3} - or -
(CH ₂ ) ₂ —.

The compound (I) of the present invention is a preferred form in the following cases. (1) In the general formula (I), R ¹ is a heterocyclic group which may be substituted, and for example, the heterocyclic group is composed of a nitrogen atom, an oxygen atom and a sulfur atom other than carbon as the ring-constituting atom. 5- or 6-membered ring containing 1 to 4 selected atoms, or (ii) such 5- or 6-membered ring and 6-membered ring containing 1 or 2 nitrogen atoms, benzene ring or 1 nitrogen In the case of a condensed ring with a 5-membered ring containing atoms (more preferably, an azolyl group). (2) In the general formula (I), A is a heterocyclic group which may be substituted, and for example, the heterocyclic group is selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon as the ring-constituting atom (i). A 5- or 6-membered ring containing 1 to 4 atoms, or (ii) such a 5- or 6-membered ring and a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or 1 nitrogen atom A condensed ring with a 5-membered ring containing (more preferably, an azolyl group, an azolinyl group or an azolidinyl group)
If it is. (3) In the general formula (I), A may be a substituted hydroxy group, more preferably (i) hydroxy group, (ii) C _1-10 alkoxy group, (iii) C _2-10 alkenyloxy group. , (Iv) a C _7-10 aralkyloxy group,
(V) C _2-13 acyloxy group, (vi) C _6-14 aryloxy group optionally substituted by 1 or 2 halogens or C _1-4 alkoxy, or (vii) C _1-10 alkylsulfonyloxy group If it is a group. (4) In the general formula (I), Y is a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms, more preferably 2 carbon atoms.
To a divalent aliphatic hydrocarbon group of 4;

(5) In the general formula (I), R ¹ is (i)
Halogen atom, (ii) imidazolyl, pyrazolyl, which may have 1 to 3 substituents selected from C _1-10 alkyl, C _6-14 aryl and C _1-10 alkylthio,
1,2,4-triazolyl, 1,2,3-triazolyl, benzimidazolyl, pyrrolidinyl, piperidinyl, morpholinyl or hexamethyleneiminyl group,
(Iii) C _1-10 alkoxy group, (iv) C _6-14 aryloxy group, (v) C _1-10 alkylthio group, (vi) C _1-6 optionally C _6-14 optionally substituted with alkyl An arylthio group,
(Vii) a thiol group substituted with imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or pyridyl optionally substituted with C _1-6 alkyl or C _6-14 aryl, (viii) A pyridyl-C _1-4 alkylthio group, or (ix) an amino group optionally substituted with 1 or 2 C _1-10 alkyl or C _3-10 cycloalkyl; A is (i) a formyl group, (ii ) C _1-10 alkyl _optionally substituted imidazolyl, pyrazolyl, 1,
2,4-triazolyl, 1,2,3-triazolyl, thiazolidinyl, oxazolinyl, thiazolinyl, 2,4
-Dioxoimidazolidinyl, 2,4-dioxooxazolidinyl or 2,4-dioxothiazolidinyl group,
(Iii) hydroxy group, (iv) C _6-14 aryloxy group optionally substituted by C _1-4 alkoxy, (v) C _1-10
Alkylsulfonyloxy group, (vi) C _1-4 alkoxy-carbonyl group, (vii) C _7-9 aralkyloxy-carbonyl group, or (viii) formula: —CON (R ⁵ ) (R
⁶ ) [In the formula, R ⁵ and R ⁶ are each a hydrogen atom or C
_1-10 alkoxy or C _1-10 alkyl which may be substituted with halogen] is shown; B is a phenyl group which may be substituted with halogen; and Y is-(CH
_{2) 2 -, - (CH} 2) 3 -, - (CH 2) 4 -, - (C
H ₂ ) ₅ − or — (CH ₂ ) ₆ −.

(6) In the general formula (I), R ¹ may be a substituted heterocyclic group; A may be a substituted heterocyclic group; and Y is a divalent C 1-7 divalent group. When it is an aliphatic hydrocarbon group. (7) In the case (6), the heterocyclic group represented by R ¹ and A is an azolyl group, an azolinyl group or an azolidinyl group. (8) In the above (6), the heterocyclic group represented by R ¹ is an azolyl group and the heterocyclic group represented by A is an azolyl group, an azolinyl group or an azolidinyl group. (9) In the above (7), the azolyl group, azolinyl group and azolidinyl group represented by R ¹ and A are pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4.
-Oxadiazolyl, 1,2,4-triazolyl, 1,
2,3-triazolyl, tetrazolyl, pyrrolidinyl,
When it is an oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl or thiazolinyl group.

(10) In the above (6), R ¹ is an azolyl which may have 1 to 3 substituents selected from C _1-10 alkyl, C _6-14 aryl and C _1-10 alkylthio. If it is a group. (11) In the above (10), the azolyl group is imidazolyl, pyrazolyl, 1,2,4-triazolyl or 1,
When it is a 2,3-triazolyl group. (12) In the above (6), A is 1 or 2 C _1-10
An azolyl, azolinyl or azolidinyl group which may be substituted with an alkyl or oxo group, more preferably imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1, which may be substituted with a C _1-10 alkyl
2,3-triazolyl, thiazolidinyl, oxazolinyl, thiazolinyl, 2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinyl or 2,4-
When it is a dioxothiazolidinyl group.

(13) In the above (6), B is a phenyl group which may be substituted, more preferably a phenyl group which may be substituted with halogen. (14) In the above (6), Y is a divalent aliphatic hydrocarbon group having 3 to 5 carbon atoms, more preferably - (CH _{2)
3 -, - (CH 2)} 4 - or - (CH _{2) 5} - if it. (15) In the general formula (I), R ¹ may be a substituted heterocyclic group; A may be a substituted hydroxy group; and Y is a divalent aliphatic hydrocarbon having 1 to 7 carbon atoms. If it is a group.

(16) In the above (15), the heterocyclic group represented by R ¹ is an azolyl group (for example, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1 , 2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl group). (17) In the above (15), R ¹ is C _1-10 alkyl, C
1 selected from _6-14 aryl and C _1-10 alkylthio
To an azolyl group which may have 3 substituents (for example, an imidazolyl group, a pyrazolyl group, a 1,2,4-triazolyl group, a 1,2,3-triazolyl group, etc.).

(18) In the above (15), A is (i) hydroxy group, (ii) C _1-10 alkoxy group, (iii) C
_2-10 alkenyloxy group, (iv) C _7-10 aralkyloxy group, (v) C _2-13 acyloxy group, (vi) 1 or 2
C _6-14 aryloxy group optionally substituted with one halogen or C _1-4 alkoxy, or (vii) C _1-10 alkylsulfonyloxy group, and more preferably a hydroxy group. (19) In the above (15), B is a phenyl group which may be substituted, and more preferably a phenyl group which may be substituted by halogen. (20) In the above (15), Y is a divalent aliphatic hydrocarbon group having 3 to 5 carbon atoms, more preferably, - (CH _{2) 3
-, - (CH 2) 4} - or - (CH _{2) 5} - if it. (21) In formula (I), 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-
Oxazole propanol or a salt thereof, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolebutanol or a salt thereof, 4-
(4-chlorophenyl) -5- [3- (1-imidazolyl) propyl] -2- (2-methyl-1-imidazolyl) oxazole or a salt thereof, 4- (4-chlorophenyl) -2- (2-methyl-) 1-imidazolyl) -5-
Oxazole pentanol or its salt, or 4-
(4-chlorophenyl) -5- [4- (1-imidazolyl) butyl] -2- (2-methyl-1-imidazolyl)
When it is oxazole or a salt thereof.

The salt of compound (I) of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base,
Examples thereof include salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Among these salts, sodium salt and potassium salt are most preferable.
Further, the compound (I) of the present invention or a salt thereof may be a hydrate.

The compound (I) of the present invention or a salt thereof (hereinafter simply referred to as the compound of the present invention) has, for example, a hypoglycemic action and an insulin secretagogue action. The compound of the present invention may be used as it is or in a mixture with pharmaceutically acceptable carriers, excipients, fillers and the like known per se, to give mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse). , Pigs, monkeys, etc.), insulin secretagogues, diabetes preventive / therapeutic agents, anti-atherogenic agents, anti-hyperlipidemic agents,
It can be used as a hypotensive agent and a prophylactic / therapeutic agent for diabetic complications (eg, nephropathy, retinopathy, neuropathy, etc.). The compound of the present invention has low toxicity, and is described in, for example, Example 36 described later.
When the compound obtained in 1. was orally administered to mice at a rate of 1 g / kg per day, no death was observed even after 5 days. The compound of the present invention is usually a tablet, capsule (including soft capsule and microcapsule), powder,
It is orally administered as granules or the like, but in some cases, it can be parenterally administered as injections, suppositories, pellets and the like. The dose of the compound of the present invention varies depending on the administration subject, administration route, symptoms, etc., but when orally administered to an adult diabetic patient, for example, the dose is 1 to 500 mg / kg, preferably 10 to 150 mg / kg per day. It is desirable to administer the amount once to three times daily.

The pharmaceutical composition of the present invention can be produced by mixing the compound of the present invention with a pharmaceutically acceptable carrier. The pharmaceutical composition is produced by a method conventionally used in the field of formulation. Examples of the pharmaceutical composition include solid preparations such as tablets, capsules, granules and powders; and liquid preparations such as syrups and injections, which are orally or parenterally administered to the mammal. Can be administered to. The pharmaceutical composition of the present invention comprises an insulin secretagogue, a therapeutic agent for diabetes, an antiarteriosclerotic agent, an antihyperlipidemic agent, an antihypertensive agent and a diabetic complication (eg, nephropathy, retinopathy,
It is preferably used as a prophylactic / therapeutic agent for neuropathy and the like, and especially as an insulin secretagogue or a therapeutic agent for diabetes treatment.

Further, the compound of the present invention can be administered to the same subject at the same time as other therapeutic agents for diabetes, therapeutic agents for diabetic complications, antihyperlipidemic agents or antihypertensive agents, etc. It can also be administered to a subject. Here, as a therapeutic agent for diabetes, an insulin sensitivity enhancer (eg, pioglitazone, troglitazone, BRL-
49653 etc.), α-glucosidase inhibitors (for example,
Voglibose, acarbose, miglitol, etc.) or biguanide agents (eg, phenformin, metformin, buformin, etc.) and the like. As a therapeutic agent for diabetic complications, an aldose reductase inhibitor (for example,
Torrestat, Epalrestat, Zenarestat, etc.). As an anti-hyperlipidemic agent, a statin compound that is a cholesterol synthesis inhibitor (for example, pravastatin, simvastatin, lovastatin, cerivastatin, etc.), a squalene synthase inhibitor, or a fibrate compound that has a triglyceride lowering action (for example, bezafibrate) Etc. Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, losartan, candesartan cilexetil, etc.) and the like. When the compound of the present invention is used in combination with another agent, the compounding ratio is, administration subject, age and weight of administration subject, symptoms, administration time,
It can be appropriately selected depending on the dosage form, administration method, combination and the like.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations, It is added as a solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol,
Examples thereof include trehalose, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, tricaprylin and the like. Suitable examples of the solubilizing agent include, for example, polyethylene glycol, propylene glycol,
D-mannitol, trehalose, benzyl benzoate,
Examples include ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include:
For example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin,
Surfactants such as benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc .; for example polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
Examples include hydrophilic polymers such as hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Suitable examples of preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol,
Examples include phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The compound (I) of the present invention can be produced by a method known per se. As such a method, for example, the method described below or a method analogous thereto and JP-A-58-183676 and JP-A-59-1 are used.
The method described in 90979 etc. or a method similar thereto can be used. In the compound (I), the compound represented by the general formula (I-
a):

Embedded image [In the formula, R ^1a is a halogen atom, and other symbols have the same meanings as described above. ] The compound or salt thereof represented by the general formula

Embedded image [The symbols in the formula are as defined above. ] It can manufacture by reacting the compound or its salt represented by these, and a halogenating agent, Moreover, General formula (Ib):

Embedded image [In the formula, R ^1b is an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, and other symbols are as described above. Show the same meaning. ] The compound or salt thereof represented by the formula] is a compound or salt thereof represented by the general formula (Ia) and a general formula: R ^1b -H [wherein the symbols have the same meanings as defined above]. ] It can manufacture by reacting with the compound represented by these, or its salt. The definition of each substituent represented by R ^1a and R ^1b is the same as that defined for R ¹ . Specifically, compound (I) can be produced by the production method represented by Method A to Method T or the like. Method A

Embedded image [In the formula, R ² represents an alkyl group having 1 to 5 carbon atoms, X represents a halogen atom, and other symbols have the same meanings as described above. ] The alkyl group having 1 to 5 carbon atoms represented by R ² includes R ¹
Alternatively, among the alkyl groups exemplified as the substituent of the heterocyclic group represented by A, those having 1 to 5 carbon atoms can be mentioned. X
Examples of the halogen atom represented by include chlorine, fluorine and bromine. In the compound (I), the compound (I-1) in which R ¹ is a halogen atom and A is an esterified carboxyl group is:
For example, it is produced by subjecting compound (II) to a halogenation reaction. This reaction is usually performed in the presence of a halogenating agent, in a solvent that does not influence the reaction. The reaction may be carried out using an excess halogenating agent as a solvent. Examples of the halogenating agent include phosphorus oxychloride, phosphorus trichloride,
Examples thereof include phosphorus pentachloride, thionyl chloride, phosphorus tribromide and the like. The amount of halogenating agent used is 1 with respect to compound (II).
It is -10 molar equivalents, preferably 3-6 molar equivalents. Examples of the solvent that does not affect the reaction include benzene and
Aromatic hydrocarbons such as toluene and xylene; pyridine, a mixed solvent thereof, and the like. The reaction temperature is usually about 20 to 180 ° C, preferably about 50 to 13 ° C.
The reaction time is about 0.5 to 20 hours at 0 ° C. The compound (I-1) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

Method B

[Chemical 12] [In the formula, each symbol has the same meaning as described above. In the compound (I), the compound (I-3) in which A is a carboxyl group is produced, for example, by subjecting the compound (I-2) to a hydrolysis reaction. This reaction is carried out in the presence of an acid or a base in a water-containing solvent according to a conventional method. Examples of the water-containing solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and a mixed solvent of dimethyl sulfoxide, acetone and the like and water. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like. Examples of the base include potassium carbonate, sodium carbonate, sodium methoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide and the like. Acid or base is compound (I-2)
Excess (base: about 1.2 to 5 equivalents, acid: about 2 to 5)
It is preferable to use 0 equivalent). The reaction temperature is usually
About -20 to 150 ° C, preferably about -10 to 100 ° C,
The reaction time is about 0.1 to 20 hours. The compound (I-3) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method C

Embedded image [In the formula, R ³ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, Z represents an optionally substituted heterocycle, hydroxy, thiol or amino group, and other symbols have the same meanings as described above. . ] The alkyl group having 1 to 5 carbon atoms represented by R ³ includes R ¹
Alternatively, among the alkyl groups exemplified as the substituent of the heterocyclic group represented by A, those having 1 to 5 carbon atoms can be mentioned. Z
Examples of the optionally substituted heterocycle, hydroxy, thiol or amino group represented by are the optionally substituted heterocycle, R ¹ , hydroxy or thiol or amino group represented by R ¹ .

In the compound (I), the compound (I-5) wherein R ¹ is a heterocyclic ring which may be substituted, hydroxy, thiol or amino group, and A is an optionally esterified carboxy group, For example, it is produced by reacting compound (I-4) with compound (XI). This reaction is generally performed in the presence of a base, in a solvent that does not influence the reaction. Further, in the compound (XI), when Z is an amino group which may be substituted, excess compound (XI) can be used as a solvent. Examples of the solvent that does not influence the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; N, N-dimethylformamide,
Examples thereof include dimethyl sulfoxide, acetone, water and mixed solvents thereof. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; metal hydrides such as sodium hydride; sodium methoxide, sodium ethoxide and the like. Can be mentioned. The amount of compound (XI) used is usually compound (I-4)
To about 1 to 10 molar equivalents. In addition, the compound (X
In I), when Z is an optionally substituted amino group, the amount of the compound (XI) used is usually the compound (I-4).
To about 1 to 50 molar equivalents. The reaction temperature is usually about 20 to 180 ° C, preferably about 80 to 140 ° C,
The reaction time is about 0.5 to 20 hours. The compound (I-5) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like.

Method D

Embedded image [In the formula, R ⁴ represents an alkyl, aralkyl, heteroarylalkyl or acyl group, and other symbols have the same meanings as described above. ] Alkyl represented by R ^4, aralkyl, examples of heteroarylalkyl or acyl group, exemplified alkylthio group as a thiol group that may be substituted represented by R ^1, aralkylthio group, in heteroarylalkylthio group or an acylthio group Examples thereof include an alkyl group, an aralkyl group, a heteroarylalkyl group and an acyl group. In the compound (I), the compound (I-6) in which R ¹ is a substituted thiol group and A is an optionally esterified carboxy group is reacted with, for example, the compound (III) and the compound (XII). It is manufactured by This reaction is carried out in the presence of a base, in a solvent that does not influence the reaction. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; metal hydrides such as sodium hydride; sodium methoxide, sodium ethoxide and the like. Can be mentioned. Examples of the solvent that does not influence the reaction include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene and xylene; N, N-dimethylformamide, dimethylsulfoxide, acetone, water, and mixed solvents thereof. Can be mentioned. The amount of compound (XII) used is approximately 1 to 10 molar equivalents relative to compound (III). The reaction temperature is generally about −20 to 150 ° C., preferably about 0 to 100 ° C., and the reaction time is about 0.1 to 20 hours. The compound (I-6) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method E

Embedded image [In the formula, Y ¹ represents a divalent aliphatic hydrocarbon group, and other symbols have the same meanings as described above. Y ¹ -CH ₂ has the same meaning as the divalent aliphatic hydrocarbon group represented by Y. In compound (I), compound (I-8) in which A is a hydroxy group can be produced, for example, by subjecting compound (I-7) to a reduction reaction. This reaction can be carried out by a method known per se. The reduction reaction is usually performed using a reducing agent in a solvent that does not affect the reaction. As the reducing agent, a metal hydride such as an alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.); a metal hydride complex compound such as lithium aluminum hydride; an organic tin such as triphenyltin hydride Compounds: diborane, substituted borane and the like can be mentioned. Examples of the solvent that does not influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride; ethers such as tetrahydrofuran and dioxane; methanol and ethanol. Alcohols such as; N, N-dimethylformamide or a mixed solvent thereof may be mentioned, and these solvents are appropriately selected depending on the kind of the reducing agent. The reaction temperature is usually about −
20 to 150 ° C., preferably about 0 to 100 ° C., and the reaction time is about 0.1 to 10 hours. The compound (I-8) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

F method

Embedded image [In the formula, each symbol has the same meaning as described above. In the compound (I), the compound (I-9) in which A is a formyl group can be produced, for example, by subjecting the compound (I-8) to an oxidation reaction. This reaction can be carried out by a method known per se. The oxidation reaction is, for example, manganese dioxide,
Chromic acid or dimethylsulfoxide is used. For example, when the oxidation reaction is carried out using dimethyl sulfoxide, the reaction is carried out in the presence of an electrophilic reagent in a solvent that does not affect the reaction. Examples of the electrophilic reagent include acetic anhydride, phosphoric anhydride, oxalyl chloride, dicyclohexylcarbodiimide, chlorine and the like. The electrophilic reagent is usually used in an equimolar amount with respect to dimethyl sulfoxide. Examples of the solvent that does not influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene. The amount of dimethyl sulfoxide used is approximately 1 to 5 molar equivalents, preferably approximately 1 to 2 molar equivalents, relative to compound (I-8). The reaction temperature is usually about -20 to
100 degreeC, Preferably it is about 0-60 degreeC, and reaction time is about 0.5-20 hours. The compound (I-9) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method G

Embedded image [In the formula, each symbol has the same meaning as described above. In compound (I), compound (I-10) in which A is a substituted hydroxy group is produced, for example, by subjecting compound (I-8) to an acylation reaction. This reaction can be carried out by a method known per se. For the acylation reaction, for example, the compound (I-8) and a carboxylic acid derivative (R ⁴ CO ₂ H) can be used.
And a condensing agent (eg, dicyclohexylcarbodiimide, etc.)
Method of directly condensing using compound or compound (I-8)
And a reactive derivative of a carboxylic acid derivative (R ⁴ CO ₂ H) are appropriately reacted. Here, as the reactive derivative of the carboxylic acid derivative (R ⁴ CO ₂ H), for example, acid anhydride, acid halide (eg, acid chloride, acid bromide, etc.), imidazolide or mixed acid anhydride (eg, methyl carbonate, Ethyl carbonate, an anhydride with isobutyl carbonate, etc.) and the like. The simplest method among these is a method using an acid chloride or an acid anhydride, in which case the reaction is carried out in the presence of a base in a solvent that does not influence the reaction. Examples of the base include triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogen carbonate, potassium carbonate, sodium carbonate and the like. Examples of the solvent that does not influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethyl acetate, tetrahydrofuran and the like. The amount of the acid chloride or acid anhydride used is approximately 1 to 5 molar equivalents relative to compound (I-8).
The reaction temperature is about -30 to 100 ° C, and the reaction time is about 0.
5 to 20 hours. The compound (I-10) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method H

Embedded image [In the formula, E is a halogen atom or OSO ₂ R ⁴ , Z ¹ is an optionally substituted heterocycle or a hydroxyl group, and other symbols have the same meanings as described above. Examples of the halogen atom represented by E include chlorine, fluorine and bromine. The optionally substituted heterocyclic or hydroxy group represented by Z ^1, include heterocyclic or hydroxy group optionally substituted represented by R ^1. In the compound (I), the compound (I-11) in which A is an optionally substituted heterocycle or a hydroxy group is:
For example, it is produced by subjecting compound (IV or I-20) and compound (XIII) to a condensation reaction. This reaction is carried out according to a conventional method in the presence of a base, in a solvent that does not influence the reaction. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; pyridine, triethylamine, N,
Examples include amines such as N-dimethylaniline; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium ethoxide, potassium t.-butoxide, and the like. The amount of these bases used is preferably 1 to 5 molar equivalents relative to compound (IV or I-20). Examples of the solvent that does not influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; halogenated carbonization such as chloroform and dichloromethane. Hydrogens;
Examples thereof include N, N-dimethylformamide, dimethyl sulfoxide and a mixed solvent thereof. The reaction temperature is generally about -50 to 150 ° C, preferably about -10 to 100 ° C.
C, reaction time is about 0.5 to 20 hours. The compound (I-11) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method I

Embedded image [In the formula, each symbol has the same meaning as described above. In the compound (I), the compound (I-11) in which A is an optionally substituted heterocycle or a hydroxy group can be obtained by subjecting the compound (I-8) and the compound (XIII) to a condensation reaction, for example. Is also manufactured. This reaction is carried out according to a conventional method in the presence of an organic phosphorus compound and an electrophilic agent, in a solvent that does not influence the reaction. Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine. Examples of the electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonyldipiperazine. The amount of the organic phosphorus compound and the electrophilic agent used is the compound (I-
It is preferably about 1 to 5 molar equivalents with respect to 8). Examples of the solvent which does not influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N- Examples thereof include dimethylformamide, dimethylsulfoxide and a mixed solvent thereof. The reaction temperature is usually about −50 to 150 ° C., preferably about −
The reaction time is about 0.5 to 20 hours at 10 to 100 ° C. The compound (I-11) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

J method

Embedded image [In the formula, each symbol has the same meaning as described above. In the compound (I), the compound (I-12) in which A is an amidated carboxy group is a compound (I-7) or a compound (X
It is produced by reacting with IV). Compound (I-
In 7), when R ³ is an alkyl group having 1 to 5 carbon atoms, the reaction is carried out in a solvent that does not affect the reaction or without a solvent. Examples of the solvent that does not influence the reaction include alcohols such as methanol and ethanol; aromatic hydrocarbons such as toluene and xylene; pyridine, N, N-dimethylformamide, dimethyl sulfoxide and the like. The amount of compound (XIV) used is
It is preferably used in excess with respect to the compound (I-7).
The reaction temperature is usually about 20 to 200 ° C., and the reaction time is about 0.1 to 20 hours.

In the compound (I-7), when R ³ is a hydrogen atom, the reaction is a direct condensation of the compound (I-7) with the compound (XIV) using a condensing agent (eg, dicyclohexylcarbodiimide). Or a method of appropriately reacting the reactive derivative of the compound (I-7) with the compound (XIV). Here, as the reactive derivative of the compound (I-7), for example, acid anhydride, acid halide (acid chloride, acid bromide), imidazolide or mixed acid anhydride (for example, methyl carbonate, ethyl carbonate, isobutyl carbonate Things) and so on. The simplest method among these is a method using an acid halide or a mixed acid anhydride. For example, when using an acid halide, the reaction is carried out in the presence of a base in a solvent that does not influence the reaction. Examples of the base include triethylamine and N-
Methylmorpholine, N, N-dimethylaniline, sodium hydrogen carbonate, potassium carbonate, sodium carbonate and the like can be mentioned. Examples of the solvent that does not influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethyl acetate, tetrahydrofuran, water, and mixed solvents thereof. The amount of compound (XIV) used is approximately 1 to 1.5 molar equivalents relative to compound (I-7). The reaction temperature is usually about -30 to 100 ° C, and the reaction time is about 0.5 to 20 hours. When a mixed acid anhydride is used, compound (I-7) and a chlorocarbonic acid ester (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) are combined with a base (eg, triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogen carbonate, potassium carbonate, sodium carbonate and the like), and further reacted with compound (XIV). The amount of compound (XIV) used is approximately 1 to 1.5 molar equivalents relative to compound (I-7). This reaction is carried out in a solvent that does not influence the reaction, and examples of such a solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethyl acetate and tetrahydrofuran. , Water, a mixed solvent thereof, or the like. The reaction temperature is usually about -30 to 50 ° C, and the reaction time is about 0.5 to 20 hours. The compound (I-12) thus obtained is
It can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

K method

[Chemical 21] [In the formula, n represents 2 or 3, and other symbols have the same meanings as described above. In the compound (I), A is a compound (I-
14) is produced by subjecting compound (I-13) to a ring closure reaction. This reaction is carried out in the presence of a base, in a solvent that does not influence the reaction. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; amines such as pyridine, triethylamine and N, N-dimethylaniline;
Metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium ethoxide, potassium t.-butoxide and the like can be mentioned. The amount of these bases to be used is preferably about 1-5 relative to compound (I-13).
It is a molar equivalent. Examples of the solvent that does not influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; halogenated carbonization such as chloroform and dichloromethane. Hydrogen; N, N-dimethylformamide, dimethylsulfoxide, and a mixed solvent thereof are included. The reaction temperature is generally about -50 to 150 ° C, preferably about -10.
The reaction time is about 0.5 to 20 hours at 100 ° C. The compound (I-14) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

L method

Embedded image [In the formula, R ⁷ represents an alkyl, aralkyl, aryl or heteroarylalkyl group, and other symbols have the same meanings as described above. ] Alkyl represented by R ^7, aralkyl, aryl or heteroarylalkyl group, the alkoxycarbonyl group in the illustrated esterified carboxyl group as the substituents for R ¹ or A, an aralkyloxycarbonyl group, an aryloxycarbonyl group, or Mention may be made of an alkyl, aralkyl, aryl or heteroarylalkyl group in the heteroarylalkyloxycarbonyl group. In the compound (I), the compound (I-15) in which A is an esterified carboxy group is
For example, it is produced by reacting compound (I-3) with compound (XV). This reaction is carried out according to a conventional method in the presence of a base, in a solvent that does not influence the reaction. Examples of the base include potassium hydroxide, sodium hydroxide,
Lithium hydroxide, sodium hydrogen carbonate, potassium carbonate,
Alkali metal salts such as sodium carbonate; metal hydrides such as sodium hydride; sodium methoxide, sodium ethoxide and the like. Examples of the solvent that does not influence the reaction include ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; N, N-dimethylformamide, dimethylsulfoxide and a mixed solvent thereof. The amount of compound (XV) used is preferably about 1-10 molar equivalents relative to compound (I-3). The reaction temperature is usually about −
20 to 150 ° C., preferably about 0 to 100 ° C., and the reaction time is about 0.5 to 20 hours. The compound (I-15) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method M

Embedded image [In the formula, each symbol has the same meaning as described above. The compound (I-16) can be synthesized by dehydroxylating the compound (XVI). This method is carried out by directly reducing with a silane compound or by halogenating the hydroxy group of compound (XVI) and then reducing. When reducing directly with a silane compound, for example, compound (XVI) in trifluoroacetic acid is added to triethylsilane [(C ₂ H ₅ ) ₃ SiH] or diethylsilane [(C ₂ H ₅ ) ₂ SiH ₂ ].
It is advantageously carried out by reacting with Examples of the halogenating agent used in this method include thionyl chloride, phosphorus tribromide and the like, and as the reducing agent, it is preferable to use a metal such as iron and zinc in hydrochloric acid or acetic acid. The compound (I-16) thus obtained can be isolated and purified by known purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compound (XVI) of Method M is produced, for example, by Method N below. N method

Embedded image [In the formula, each symbol has the same meaning as described above. In this method, first, the compound (XVII) is condensed with the compound (XVIII) to produce the compound (XIX). This reaction is carried out in the same manner as in the method of producing compound (VII) by condensing compound (V) and compound (VI) shown in Method R. Then, the compound (XIX) is halogenated to produce the compound (XX). This reaction is carried out in the same manner as the halogenation reaction of compound (II) shown in Method A. The compound (XXI) is produced by reacting the compound (XX) thus obtained with the compound (XI). This reaction is carried out in the same manner as in the method of producing compound (I-5) by reacting compound (I-4) and compound (XI) shown in Method C. Then, the compound (XXI) is reduced to produce the compound (XVI). This reaction can be carried out in the same manner as in the reduction reaction shown in Method E. The compound (XV
I) can be isolated and purified by a known purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method O

Embedded image [In the formula, each symbol has the same meaning as described above. In the compound (I), a compound (I-1
7) is produced, for example, by reacting compound (I-9) with compound (XXII). This reaction is carried out according to a conventional method in the presence of an acid or a salt thereof in a solvent that does not influence the reaction. Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, p-toluenesulfonic acid and the like, and examples of the salt include sodium acetate, pyridine p-toluenesulfonic acid and the like. The amount of these acids or salts thereof used is, for example, about 0.1 to 2 molar equivalents relative to compound (I-9).
Examples of the solvent that does not influence the reaction include aromatic hydrocarbons (eg, benzene, toluene), tetrahydrofuran, acetic acid and the like. The reaction temperature is usually about −
The reaction time is about 0.5 to 20 hours at 20 to 200 ° C, preferably about 0 to 150 ° C. The compound (I-17) thus obtained can be isolated and purified by known purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method P

[Chemical formula 26] [In the formula, each symbol has the same meaning as described above. In the compound (I), a compound (I-1
8) can be produced, for example, by reacting compound (XXIV) with compound (XXV). This reaction is carried out according to a conventional method in a solvent that does not influence the reaction. Examples of the solvent that does not influence the reaction include alcohols (eg, methanol, ethanol, propanol, isopropanol), aromatic hydrocarbons (eg, benzene, toluene), tetrahydrofuran, N, N-dimethylformamide, pyridine, acetic acid. And so on.
The reaction temperature is generally about -20 to 200 ° C, preferably 0.
At ~ 150 ° C, the reaction time is about 0.5-20 hours.
The compound (I-18) thus obtained can be isolated and purified by a known purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compound (XXIV) of Method P is produced, for example, by Method Q below. Q method

Embedded image [In the formula, each symbol has the same meaning as described above. Compound (XXIV) is produced, for example, by subjecting compound (I-19) to a dehydration reaction. This reaction is carried out according to a conventional method in the presence of a dehydrating agent, in a solvent that does not influence the reaction. Examples of the dehydrating agent include sulfuric acid, acetic anhydride, phosphorus pentoxide, phosphorus oxychloride and the like. Examples of the solvent that does not influence the reaction include alcohols (eg, methanol, ethanol, propanol, isopropanol), aromatic hydrocarbons (eg, benzene, toluene), tetrahydrofuran, N, N-dimethylformamide and the like. . The reaction temperature is usually about -20.
-200 ° C, preferably 0-150 ° C, the reaction time is about 0.5-20 hours. The compound (XXIV) thus obtained can be isolated and purified by a known purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compounds (II), (III) and (IV) used for producing the above-mentioned compound (I) can be produced by a method known per se. As such a method, for example, the method described below or a method analogous thereto and JP-A-58-183676 and JP-A-5-183676.
The method described in 9-190979 or the like or a method similar thereto can be used. The starting compound (II) for Method A is
For example, it is manufactured by the following R method. R method

Embedded image [In the formula, each symbol has the same meaning as described above. ]

In this method, first, the compound (V) and the compound (V
Compound (VII) is produced by condensing with I). This reaction is carried out according to a conventional method in the presence of a Lewis acid, in a solvent that does not influence the reaction or in the absence of a solvent. Examples of the Lewis acid include aluminum chloride, titanium tetrachloride, tin tetrachloride, boron trifluoride and the like. The amount of these Lewis acids used is preferably about 1 to the compound (V).
It is 5 molar equivalents. Examples of the solvent that does not influence the reaction include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride;
Carbon disulfide or a mixed solvent thereof may be used. The amount of compound (VI) used is about 1 to 5 with respect to compound (V).
It is a molar equivalent, preferably about 1 to 3 molar equivalents. The reaction temperature is generally about -20 to 150 ° C, preferably about -10.
The reaction time is about 0.5 to 20 hours.

Then, the compound (VII) is subjected to a halogenation reaction to produce the compound (VIII). This reaction is carried out according to a conventional method, usually in the presence of a halogenating agent, in a solvent that does not influence the reaction. Examples of the halogenating agent include chlorine and bromine. The amount of the halogenating agent used is preferably about 1-1.5 molar equivalents relative to compound (VII). Examples of the solvent that does not affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as dichloromethane and chloroform; acetic acid or a mixed solvent thereof. The reaction temperature is usually about -20.
-150 ° C, preferably about -10 to 80 ° C, and the reaction time is about 0.5 to 20 hours. The compound (VIII) thus obtained is reacted with an organic acid salt in a solvent that does not affect the appropriate reaction to produce the compound (IX).
Examples of the organic acid salt include sodium formate, potassium formate, sodium acetate and the like. The amount of the organic acid salt used is approximately 1 to 20 molar equivalents, preferably approximately 2 to 10 molar equivalents, relative to compound (VIII). Examples of the solvent that does not influence the reaction include alcohols such as methanol and ethanol. The reaction temperature is generally about 0 to 150 ° C., preferably about 30 to 100 ° C., and the reaction time is about 1 to 50 hours.

Then, compound (IX) is reacted with chlorocarbonic acid ester to produce compound (X). This reaction is carried out according to a conventional method in the presence of a base, in a solvent that does not influence the reaction. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; pyridine, triethylamine,
Examples include amines such as N, N-dimethylaniline. The amount of these bases used is preferably about 2-5 molar equivalents relative to compound (IX). Examples of the solvent that does not influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; N, N-dimethylformamide, Dimethyl sulfoxide and a mixed solvent thereof may be mentioned. The reaction temperature is usually about -50 to 150.
C., preferably about −30 to 50 ° C., the reaction time is about 0.
5 to 20 hours.

Further, compound (X) is reacted with ammonia or a salt thereof to produce compound (II). The reaction is
It is usually carried out in a solvent that does not affect the reaction. Examples of ammonia or salts thereof include ammonia gas and ammonium acetate. For example, when using an ammonium salt, the amount used is relative to compound (X)
It is about 1 to 20 molar equivalents. Examples of the solvent that does not influence the reaction include ethers such as tetrahydrofuran and dioxane; acetic acid or a mixed solvent thereof. The reaction temperature is generally about 0 to 150 ° C., preferably about 50 to 120 ° C., and the reaction time is about 0.5 to 20 hours. The compound (II) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compound (III) for Method D is produced, for example, by Method S below. S method

[Chemical 29] [In the formula, each symbol has the same meaning as described above. The compound (III) is produced by reacting the compound (I-1) with thiourea, thioacetic acid or a salt thereof in the presence of a base in a solvent that does not affect the appropriate reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydrogen carbonate and potassium carbonate. As the solvent that does not influence the reaction, for example, tetrahydrofuran,
Ethers such as dioxane; and a mixed solvent of N, N-dimethylformamide or dimethylsulfoxide and water. The amount of thiourea, thioacetic acid or its salt to be used is about 1-20 molar equivalents, preferably about 2-10 molar equivalents, relative to compound (I-1). The reaction temperature is usually
About 0 to 150 ° C, preferably about 50 to 120 ° C, and the reaction time is about 0.1 to 20 hours. The compound (III) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compound (IV) of Method H is produced, for example, by Method T below. T method

Embedded image [In the formula, each symbol has the same meaning as described above. The compound (IV) in which E is a halogen atom is, for example, the compound (I-8) and a halogenating agent, and the compound (I-20) in which E is OSO ₂ R ⁴ is, for example, the compound (I-8). ) And a sulfonylating agent. When a halogenating agent is used, thionyl chloride, phosphorus tribromide and the like are preferable as the halogenating agent. In this case, a compound (IV) in which E is chlorine or bromine is produced. The amount of halogenating agent used is approximately 1 to 20 with respect to compound (1-8).
It is a molar equivalent. The reaction is usually performed in a solvent that does not affect the reaction (eg, benzene, toluene, chloroform, dichloromethane, etc.). Also, an excess halogenating agent may be used as a solvent. The reaction temperature is generally about −20 to 150 ° C., preferably about 10 to 100 ° C., and the reaction time is about 0.1 to 20 hours. When a sulfonylating agent is used, for example, mesyl chloride, tosyl chloride, benzenesulfonyl chloride and the like are preferable as the sulfonylating agent. In this case, a compound (I-20) in which E is mesyloxy, tosyloxy or benzenesulfonyloxy is produced. The reaction is usually performed in a solvent that does not influence the reaction, preferably in the presence of an appropriate base. Examples of the solvent that does not influence the reaction include aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane; ethyl acetate, tetrahydrofuran and the like. Examples of the base include triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogen carbonate, potassium carbonate, sodium carbonate and the like.
The amount of the sulfonylating agent and the base used is the compound (I-8)
To about 1 to 1.5 molar equivalents, respectively. The reaction temperature is generally about -20 to 150 ° C, preferably about 10
The reaction time is about 0.1 to 20 hours at 100 ° C. Compound (IV) or (I-20) thus obtained
Can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[0059]

[Table 1]

──────────────────────────────── Compound Blood glucose lowering rate (%) (Example number) 60 minutes later 120 minutes After ─────────────────────────────── 15 22 22 26 25 25 38 27 27 26 32 27 27 28 24 33 33 31 27 27 28 32 25 25 28 34 27 25 36 36 23 18 ─────────────────────────────── Thus, the compound (I) of the present invention is Since it has an excellent blood glucose (blood glucose) lowering effect, it is useful as a preventive and / or therapeutic agent for diabetes.

Test Example 2 Insulin Secretion-Promoting Action on MIN6 Cells Pancreatic beta cell tumor-derived cell line MIN6 was placed in a 12-well culture plate in an incubator (37 ° C.) using a medium (DMEM) containing 15% fetal bovine serum. The cells were cultured in 5% CO ₂ ) until they became approximately 90% confluent. Cells were washed twice with buffered saline and pre-incubated with KRH medium containing 0.1 mM glucose for 30 minutes at 37 ° C. Then KRH containing 12.5 mM glucose and 10 μM test compound (controls without test compound)
The cells were cultured in the medium at 37 ° C for 2 hours. The medium is collected and a commercially available radioimmunoassay kit (Shionoria insulin,
The amount of insulin was quantified by Shionogi Pharmaceutical Co., Ltd. The plate was washed with buffered saline and the method of Lowry et al. (J. Bio
Chem., 193, 265-275, 1951) to quantify the protein content of the cells. The insulin secretion amount of the compound group was expressed as a relative value (%) with respect to the control group, and is shown in [Table 2]. [Table 2] ─────────────────────────────── Compound Insulin secretagogue (Example number) (%) ── ───────────────────────────── 36 272 65 397 72 303 303 83 359 89 385 ─────────── ───────────────────── Thus, since the compound (I) of the present invention has an excellent insulin secretagogue action, it is useful as a therapeutic agent for diabetes prevention. is there.

[0061]

【Example】

Reference Example 1 Methyl 4- (4-chlorobenzoyl) butyrate (70.0
g) in dichloromethane (400 ml) in bromine (4
6.5 g) was added dropwise. After stirring 15 minutes, the reaction mixture is washed with water, dried (MgSO _4), concentrated to give 4-bromo-4- (4-chlorobenzoyl) butyrate (89.5
g, yield 96%) was obtained as an oil. NMR (δ ppm in
CDCl ₃ ): 2.3 to 2.7 (4H, m), 3.71 (3H, s), 5.33 (1H, dd, J = 8
& 5.5Hz), 7.48 (2H, d, J = 8.5Hz), 7.98 (2H, d, J = 8.5Hz). Reference Example 2 A mixture of methyl 4-bromo-4- (4-chlorobenzoyl) butyrate (89.5 g), sodium formate (76.2 g) and methanol (400 ml) was stirred under reflux for 12 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry (Mg
SO ₄₎ After the solvent was distilled off, 4- (4-chlorobenzoyl) -4-hydroxybutyrate (72.0 g, yield: 1
00%) as an oil. This oil (72.0
g) was dissolved in tetrahydrofuran (400 ml), pyridine (22.2 g) was added, and phenyl chlorocarbonate (43.8 g) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 2N hydrochloric acid, washed with water and dried (M
gSO ₄ ), the solvent is distilled off and the precipitated crystals are collected by filtration,
Methyl 4- (4-chlorobenzoyl) -4-phenoxycarbonyloxybutyrate (61.2 g, yield 58%) was obtained. Recrystallized from methanol. Colorless prism crystals. Melting point 97-98 [deg.] C.

Reference Example 3 A mixture of methyl 4- (4-chlorobenzoyl) -4-phenoxycarbonyloxybutyrate (61.2 g), ammonium acetate (62.2 g) and acetic acid (300 ml) was refluxed for 1.5 hours. Stir it. Concentrate the reaction mixture,
Water was added to the residue and the precipitated crystals were collected by filtration and recrystallized from methanol to give 3- [4- (4-chlorophenyl) -2.
Methyl -oxo-4-oxazolin-5-yl] propionate (36.6 g, 79% yield) was obtained. Colorless needles. 147-148 ° C. Reference Example 4 A mixture of methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate (5.72 g), thiourea (4.57 g) and ethanol (70 ml) was stirred under reflux for 30 minutes. A 2N sodium hydroxide aqueous solution (40 ml) was added to the reaction mixture, and the mixture was stirred under reflux for an additional 30 minutes. Water was added to the reaction mixture, which was neutralized with 6N hydrochloric acid and the precipitated crystals were collected by filtration, and 3- [4- (4-
Chlorophenyl) -2-thioxo-4-oxazoline-
5-yl] propionic acid (5.41 g, yield 96%) was obtained. Recrystallized from ethanol. Colorless needles. Melting point 1
96-197 ° C.

Reference Example 5 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolepropionamide (840 mg) in N, N-dimethylformamide (20
(ml) solution, phosphorus oxychloride (585 mg) was added dropwise at room temperature. After stirring for 1 hour, the reaction mixture was poured into ice water, neutralized with saturated aqueous sodium hydrogen carbonate and the precipitated crystals were collected by filtration.
(4-chlorophenyl) -5- (2-cyanoethyl)-
2- (2-Methyl-1-imidazolyl) oxazole (650 mg, 82%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 16
3 to 164 ° C. Reference Example 6 Adipic acid monomethyl ester chloride (17.9 g) was added dropwise to a mixture of chlorobenzene (33.8 g) and anhydrous aluminum chloride (26.7 g) under ice water. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry (Mg
SO ₄₎ After the solvent was distilled off to obtain 5- (4-chlorobenzoyl) pentanoate. This was dissolved in dichloromethane (100 ml) and bromine (16.0 g) was added dropwise. The reaction mixture was washed with aqueous sodium hydrogen sulfite solution, then water. Wash the dichloromethane layer with water and dry (MgS
O ₄₎ After the solvent was distilled off, 5-bromo-5- (4-chlorobenzoyl) pentanoate (31.7 g, 95
%) As an oil. NMR (δ ppm in CDCl ₃ ): 1.6
~ 2.3 (4H, m), 2.42 (2H, t, J = 7Hz), 3.68 (3H, s), 5.08 (1
H, dd, J = 8 & 6.5Hz), 7.47 (2H, d, J = 9Hz), 7.96 (2H, d, J = 9H)
z).

Reference Example 7 In the same manner as in Reference Example 2, methyl 5-bromo-5- (4-chlorobenzoyl) pentanoate (89.5 g) was reacted with sodium formate and then with phenyl chlorocarbonate to give 5-.
Methyl (4-chlorobenzoyl) -5-phenoxycarbonyloxypentanoate was obtained as an oil (yield 67
%). NMR (δ ppm in CDCl ₃ ): 1.8 to 2.1 (4H, m), 2.40 (2
H, t, J = 7Hz), 3.67 (3H, s), 5.82 (1H, dd, J = 7.5 & 4.5Hz),
7.15 ~ 7.45 (5H, m), 7.48 (2H, d, J = 9Hz), 7.91 (2H, d, J = 9H
z). Reference Example 8 In the same manner as in Reference Example 3, 5- (4-chlorobenzoyl)
By the reaction of methyl-5-phenoxycarbonyloxypentanoate with ammonium acetate, 4- [4- (4-chlorophenyl) -2-oxo-4-oxazoline-5-
Methyl] butanoate was obtained (yield 69%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 121-122 [deg.] C.

Reference Example 9 4- (4-chlorophenyl) -4-oxazoline-2-
Titanium tetrachloride (15.5 g) was added dropwise to a mixture of ON (4.00 g), ethyl chloroglyoxylate (5.58 g) and dichloromethane (30 ml) at room temperature. After stirring for 2 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry (Mg
SO ₄₎ After the solvent was distilled off, 2- [4- (4-chlorophenyl) -2-oxo-4-oxazolin-5-yl]
Crystals of ethyl-2-oxoacetate (5.38 g, 89%)
I got Recrystallized from ethyl acetate-hexane. Light yellow prism crystal. 152-153 ° C. Reference Example 10 2- [4- (4-chlorophenyl) -2-oxo-4-
A mixture of ethyl oxazolin-5-yl] -2-oxoacetate (2.50 g), phosphorus oxychloride (6.48 g) and pyridine (740 mg) was stirred at 120-125 ° C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry (MgS
After O ₄ ), the solvent was evaporated and the residue was subjected to silica gel column chromatography. From the ethyl acetate-hexane (1: 9, v / v) eluate, 2- [2-chloro-4]
-(4-Chlorophenyl) -5-oxazolyl] -2-
Obtained ethyl oxoacetate (450 mg, 17%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 98-99 ° C.

Reference Example 11 2- [2-chloro-4- (4-chlorophenyl) -5-
Oxazolyl] -2-oxoethyl acetate (4.63
g), 2-methylimidazole (1.45 g) and N, N-dimethylformamide (50 ml) in a mixture of sodium hydride (oil, 60%) (710 mg).
Was gradually added at 0 ° C. After stirring for 1 hour at room temperature, the reaction mixture is poured into ice water and precipitated 2- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl)
Ethyl-5-oxazolyl] -2-oxoacetate (3.1
2 g, 59%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 126-127 ° C. Reference Example 12 2- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolyl] -2-oxoethyl acetate (2.93 g) was added to tetrahydrofuran (6).
(0 ml) -2-propanol (30 ml), and sodium borohydride (95 mg) was added at 0 ° C. 3
After stirring for 0 minutes, the reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO
₄ ) After that, the solvent is distilled off and 2- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) is precipitated.
Obtained ethyl-5-oxazolyl-2-hydroxyacetate (2.20 g, 75%). Recrystallized from acetone-ethyl acetate. Colorless prism crystals. Melting point 197-198
° C (decomposition).

Reference Example 13 N, N-Dimethylformamide (1 drop) was added to a solution of pimelic acid monoethyl ester (25.5 g) in tetrahydrofuran (40 ml), and then oxalyl chloride (1
8.8 g) was added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue was converted to chlorobenzene (61.
0 g) and anhydrous aluminum chloride (36.1 g) were added dropwise under ice water. After stirring for 3 hours at room temperature,
The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ),
The solvent was evaporated, and ethyl 6- (4-chlorobenzoyl) hexanoate (37.7 g, 97%) was obtained as an oil.
NMR (δ ppm in CDCl ₃ ): 1.25 (3H, t, J = 7Hz), 1.3 to 1.9 (6
H, m), 2.32 (2H, t, J = 7.5Hz), 2.95 (2H, t, J = 7.5Hz), 4.13
(2H, q, J = 7Hz), 7.44 (2H, d, J = 8.5Hz), 7.90 (2H, d, J = 8.5H
z). Reference Example 14 In the same manner as in Reference Example 13, suberic acid monoethyl ester was reacted with oxalyl chloride and then with chlorobenzene to obtain ethyl 7- (4-chlorobenzoyl) heptanoate as an oil (yield 90%. ). NMR (δ ppm in CDC
l ₃ ): 1.25 (3H, t, J = 7Hz), 1.2〜1.9 (8H, m), 2.2〜2.4 (2
H, m), 2.93 (2H, t, J = 7.5Hz), 4.13 (2H, q, J = 7Hz), 7.43 (2
H, d, J = 8.5Hz), 7.90 (2H, d, J = 8.5Hz).

Reference Example 15 Ethyl 6- (4-chlorobenzoyl) hexanoate (3
Bromine (21.1 g) was added dropwise to a solution of 7.3 g) in dichloromethane (200 ml) at room temperature. After stirring for 30 minutes, the reaction mixture was washed with an aqueous sodium hydrogen sulfite solution, saturated aqueous sodium hydrogen carbonate and water in this order. After drying the dichloromethane layer (MgSO ₄ ), the solvent was distilled off and 6-bromo-6-
Ethyl (4-chlorobenzoyl) hexanoate (47.6
g, quantitative) was obtained as an oil. NMR (δ ppm in CDCl
₃ ): 1.25 (3H, t, J = 7Hz), 1.3 ~ 2.3 (6H, m), 2.34 (2H, t, J =
7Hz), 4.13 (2H, q, J = 7Hz), 5.06 (1H, t, J = 7Hz), 7.47 (2H,
d, J = 8.5Hz), 7.96 (2H, d, J = 8.5Hz). Reference Example 16 In the same manner as in Reference Example 15, ethyl 7- (4-chlorobenzoyl) heptanoate was reacted with bromine to give ethyl 7-bromo-7- (4-chlorobenzoyl) heptanoate as an oil ( Yield 79%). NMR (δ ppm in CDC
l ₃ ): 1.25 (3H, t, J = 7Hz), 1.2〜1.9 (8H, m), 2.2〜2.4 (2
H, m), 4.12 (2H, q, J = 7Hz), 5.06 (1H, t, J = 7Hz), 7.47 (2H,
d, J = 8.5Hz), 7.96 (2H, d, J = 8.5Hz).

Reference Example 17 Ethyl 6-bromo-6- (4-chlorobenzoyl) hexanoate (47.6 g), sodium formate (44.8 g)
And a mixture of methanol (250 ml) at reflux under 2
Stir for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and evaporated, the residue was subjected to silica gel column chromatography. From the ethyl acetate-hexane (1: 4, v / v) elution part, ethyl 6- (4-chlorobenzoyl) -6-hydroxyhexanoate (2
4.5 g, 62%) was obtained as an oil. NMR (δ ppm i
nCDCl ₃ ): 1.23 (3H, t, J = 7Hz), 1.3〜2.0 (6H, m), 2.28 (2
H, t, J = 7Hz), 3.63 (1H, d, J = 6.5Hz), 4.10 (2H, q, J = 7Hz),
4.95 ~ 5.1 (1H, m), 7.49 (2H, d, J = 8.5Hz), 7.86 (2H, d, J =
8.5Hz). Reference Example 18 In the same manner as in Reference Example 17, ethyl 7-bromo-7- (4-chlorobenzoyl) heptanoate was reacted with sodium formate in methanol to give 7- (4-chlorobenzoyl)-.
Ethyl 7-hydroxyheptanoate was obtained as an oil (yield 31%). NMR (δ ppm in CDCl ₃ ): 1.24 (3H, t, J =
7Hz), 1.3 ~ 2.0 (8H, m), 2.27 (2H, t, J = 7.5Hz), 3.63 (1H,
d, J = 6.5Hz), 4.11 (2H, q, J = 7Hz), 4.95 ~ 5.1 (1H, m), 7.4
9 (2H, d, J = 8.5Hz), 7.87 (2H, d, J = 8.5Hz).

Reference Example 19 Phenyl chlorocarbonate (14.1 g) was added to a mixture of ethyl 6- (4-chlorobenzoyl) -6-hydroxyhexanoate (24.5 g), pyridine (7.14 g) and tetrahydrofuran (200 ml). Was added dropwise while cooling. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ after the solvent was distilled off, 6- (4-chlorobenzoyl) -6-phenoxycarbonyloxy hexanoate (32.3 g, 94
%) As an oil. NMR (δ ppm in CDCl ₃ ): 1.25
(3H, t, J = 7Hz), 1.45 ~ 2.05 (6H, m), 2.32 (2H, t, J = 7Hz),
4.12 (2H, q, J = 7Hz), 5.79 (1H, t, J = 6Hz), 7.1 ~ 7.5 (7H,
m), 7.89 (2H, d, J = 8.5Hz). Reference Example 20 In the same manner as in Reference Example 19, by reacting ethyl 7- (4-chlorobenzoyl) -7-hydroxyheptanoate with phenyl chlorocarbonate, 7- (4-chlorobenzoyl) was obtained.
Ethyl -7-phenoxycarbonyloxyheptanoate was obtained as an oil (yield, quantitative). NMR (δ ppm in CD
Cl ₃ ): 1.25 (3H, t, J = 7Hz), 1.25〜2.0 (8H, m), 2.29 (2H,
t, J = 7.5Hz), 4.12 (2H, q, J = 7Hz), 5.79 (1H, t, J = 6Hz), 7.
15〜7.45 (5H, m), 7.48 (2H, d, J = 8.5Hz), 7.90 (2H, d, J = 8.
5Hz).

Reference Example 21 A mixture of ethyl 6- (4-chlorobenzoyl) -6-phenoxycarbonyloxyhexanoate (32.3 g), ammonium acetate (29.7 g) and acetic acid (150 ml) was stirred under reflux for 1 hour. It was Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give 5- [4- (4-chlorophenyl) -2-oxo-4-oxazolin-5-yl].
Ethyl pentanoate was obtained (17.7 g, 71%). Recrystallized from acetone-isopropyl ether. Colorless needles. Melting point 143-144 [deg.] C. Reference Example 22 In the same manner as in Reference Example 21, the reaction of ethyl 7- (4-chlorobenzoyl) -7-phenoxycarbonyloxyheptanoate with ammonium acetate gave 6- [4- (4-
Chlorophenyl) -2-oxo-4-oxazoline-5
-Yl] ethyl hexanoate was obtained (yield 87%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 113-114 [deg.] C.

[0072]

Example 1 3- [4- (4-chlorophenyl) -2-oxo-4-
Methyl oxazolin-5-yl] propionate (11.
3 g), phosphorus oxychloride (18.6 g) and pyridine (3.2 ml) were stirred at 120 to 130 ° C. for 80 minutes. The reaction mixture was concentrated, ice water was added, and the mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and collected by filtration and the solvent was distilled off, precipitated crystals. Recrystallized from isopropyl ether and 2-chloro-4- (4-chlorophenyl)
Methyl-5-oxazolepropionate (8.56 g,
Yield 71%) was obtained. Colorless needles. Melting point 71-72 [deg.] C. Example 2 To a solution of methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate (8.50 g) in ethanol (50 ml) was added dropwise a 1N sodium hydroxide aqueous solution (34 ml) under ice cooling. After stirring for 20 minutes under ice-cooling and 30 minutes at room temperature, 2N hydrochloric acid was added, and the precipitated crystals were collected by filtration, and 2-chloro-4- (4-chlorophenyl)-
5-Oxazolepropionic acid (8.00 g, yield 99
%) Was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 169-170 [deg.] C.

Example 3 2 parts of an ethanol solution of sodium ethoxide prepared from sodium (0.35 g) and ethanol (15 ml)
-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43g) was added and refluxed at 30.
Stir for a minute. The solvent was distilled off, water was added to the residue, and 2
The crystals precipitated by acidification with N hydrochloric acid were collected by filtration, and 4- (4-
Chlorophenyl) -2-ethoxy-5-oxazolepropionic acid (1.40 g, yield 95%) was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 148-1
49 ° C. Example 4 Sodium hydride (60%, oily, 0.60 g) was added to 2-
It was added to propanol (20 ml) and stirred at room temperature for 10 minutes. 2-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43
g) was added, and the mixture was stirred under reflux for 30 minutes. Then, water is added to the resulting reaction mixture, which is acidified with 2N hydrochloric acid, and the precipitated crystals are collected by filtration, and 4- (4-chlorophenyl) -2-
Isopropoxy-5-oxazolepropionic acid (1.
35 g, yield 87%) was obtained. Recrystallized from isopropyl ether. Colorless prism crystals. Melting point 116-117
° C.

Example 5 2-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43 g), phenol (0.
94 g), potassium carbonate (2.10 g) and N, N-
Mix a mixture of dimethylformamide (10 ml) at 140 ° C.
Stir for 3 hours. Water was added to the reaction mixture, which was acidified with 6N hydrochloric acid and the precipitated crystals were collected by filtration to give 4- (4-chlorophenyl) -2-phenoxy-5-oxazolepropionic acid (1.60 g, yield 93%). It was Recrystallized from ethyl acetate. Colorless needles. Melting point 136-137 [deg.] C. Example 6 3- [4- (4-chlorophenyl) -2-thioxo-4
-Oxazolin-5-yl] propionic acid (1.42
g) To a mixture of 2N aqueous sodium hydroxide solution (5.5 ml) and N, N-dimethylformamide (15 ml) was added methyl iodide (0.34 ml) dropwise under ice cooling. 3
After stirring for 0 minutes, water was added to the reaction mixture, acidified with 2N hydrochloric acid, and the precipitated crystals were collected by filtration to give 4- (4-chlorophenyl) -2-methylthio-5-oxazolepropionic acid (1.45 g, yield Rate of 97%). Recrystallized from ethanol. Colorless needles. 183-184 ° C.

Example 7 In the same manner as in Example 6, 4- [4- (4-chlorophenyl) -2-thioxo-4-oxazolin-5-yl] propionic acid was reacted with isopropyl iodide to give 4-
(4-chlorophenyl) -2-isopropylthio-5-
Oxazolepropionic acid was obtained (yield 80%). Recrystallized from ethanol. Colorless prism crystals. Melting point 132-
133 ° C. Example 8 Analogously to Example 6, the reaction of 3- [4- (4-chlorophenyl) -2-thioxo-4-oxazolin-5-yl] propionic acid with 2- (chloromethyl) pyridine gave 4 -(4-Chlorophenyl) -2- (2-pyridylmethylthio) -5-oxazolepropionic acid was obtained (yield 98%). Recrystallized from ethanol. Colorless prism crystals. 125-126 ° C.

Example 9 Reaction of 3- [4- (4-chlorophenyl) -2-thioxo-4-oxazolin-5-yl] propionic acid with 3- (chloromethyl) pyridine in the same manner as in Example 6. Thus, 4- (4-chlorophenyl) -2- (3-pyridylmethylthio) -5-oxazolepropionic acid was obtained (yield 96%). Recrystallized from ethanol. Colorless needles. Melting point 129-130 [deg.] C. Example 10 2-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43 g), thiophenol (0.54 ml), sodium methoxide-methanol solution (28%, 2.00 g) and methanol. (15m
The mixture of l) was stirred under reflux for 16 hours. Water was added to the reaction mixture, acidified with 2N hydrochloric acid, and the precipitated crystals were collected by filtration to give 4- (4-chlorophenyl) -2-phenylthio-5-oxazolepropionic acid (1.60 g, yield 8
9%) was obtained. Recrystallized from methanol. Colorless needles. 156-157 ° C.

Example 11 2-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43 g), 4-methylthiophenol (0.68 g), potassium carbonate (2.07 g)
And a mixture of N, N-dimethylformamide (20 ml) were stirred under a nitrogen atmosphere at 100 ° C. for 40 minutes. Water was added to the reaction mixture, acidified with 2N hydrochloric acid, and the precipitated crystals were collected by filtration, and 4- (4-chlorophenyl) -2- (4-
Methylphenylthio) -5-oxazolepropionic acid (1.73 g, yield 93%) was obtained. Recrystallized from ethanol. Colorless needles. 160-161 ° C. Example 12 As in Example 11, by reaction of 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with 4-methyl-4H-1,2,4-triazole-3-thiol. , 4- (4-chlorophenyl) -2-
(4-methyl-4H-1,2,4-triazole-3-
Ilthio) -5-oxazolepropionic acid was obtained (yield 77%). Recrystallized from ethanol. Light brown needle crystals. Melting point 186-188 [deg.] C.

Example 13 In the same manner as in Example 11, 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid and 4-phenyl-4H-1,2,4-triazole-3-thiol were added. The reaction of 4- (4-chlorophenyl) -2-
(4-phenyl-4H-1,2,4-triazole-3
-Ilthio) -5-oxazolepropionic acid was obtained (yield 61%). Recrystallized from ethanol. Colorless needles. Melting point 122-123 [deg.] C. Example 14 Analogously to Example 11, the reaction of 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with 1-phenylimidazol-2-thiol gave 4
-(4-chlorophenyl) -2- (1-phenyl-2-
Imidazolylthio) -5-oxazolepropionic acid was obtained (yield 39%). Recrystallized from ethanol. Light brown needle crystals. Melting point 185-187 [deg.] C.

Example 15 In the same manner as in Example 11, 4- (4-chlorophenyl) -2 was prepared by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with 2-mercaptopyridine. -(2-Pyridylthio) -5-oxazolepropionic acid was obtained (yield 95%). Recrystallized from ethanol. Pale yellow needles. Melting point 172-173 [deg.] C. Example 16 2-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43 g), 30% aqueous methylamine solution (4.0 ml) and 2-propanol (20).
ml) was stirred in a sealed tube at 100 ° C. for 4 hours.
The reaction mixture was concentrated, water was added to the residue, pH was adjusted to 3 with 2N hydrochloric acid, and the precipitated crystals were collected by filtration, 4- (4-
Chlorophenyl) -2-methylamino-5-oxazolepropionic acid (1.21 g, yield 86%) was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 217
~ 218 ° C.

Example 17 In the same manner as in Example 16, 4- (4-chlorophenyl) was obtained by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with dimethylamine.
2-Dimethylamino-5-oxazolepropionic acid was obtained (yield 92%). Recrystallized from ethanol. Colorless needles. Melting point 189-190 [deg.] C. Example 18 2-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43 g), morpholine (2.
A mixture of 2 ml) and 2-propanol (20 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated, water was added to the residue, pH was adjusted to 3 with 2N hydrochloric acid, and the precipitated crystals were collected by filtration to give 4- (4-chlorophenyl) -2-
Morpholino-5-oxazolepropionic acid (1.64
g, yield 98%) was obtained. Recrystallized from ethanol.
Colorless needles. 180-181 ° C.

Example 19 In the same manner as in Example 18, 4- (4-chlorophenyl) -2-cyclohexyl was prepared by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with cyclohexylamine. Amino-5-oxazolepropionic acid was obtained (yield 53%). Recrystallized from ethanol. Colorless needles. 237-238 ° C. Example 20 In a manner similar to Example 18, 4- (4-chlorophenyl) -2 was obtained by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with pyrrolidine.
-(1-Pyrrolidinyl) -5-oxazolepropionic acid was obtained (yield 99%). Recrystallized from ethanol.
Colorless needles. Melting point 199-200 [deg.] C.

Example 21 In a manner similar to Example 18, 4- (4-chlorophenyl) -2 was obtained by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with piperidine.
-Piperidino-5-oxazolepropionic acid was obtained (yield 97%). Recrystallized from ethanol. Colorless prism crystals. 185-186 ° C. Example 22 In a manner similar to Example 18, by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with 2-methylpiperidine, 4- (4-chlorophenyl) -2- (2 -Methylpiperidino) -5-oxazolepropionic acid was obtained (yield 44%). Recrystallized from isopropyl ether. Colorless prism crystals. Melting point 126
~ 128 ° C.

Example 23 In a similar manner to Example 18, 4- (4-chlorophenyl) -2- was prepared by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with hexamethyleneimine. Hexamethyleneimino-5-oxazolepropionic acid was obtained (yield 90%). Recrystallized from ethanol. Colorless prism crystals. 137-138 ° C. Example 24 2-Chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid (1.43 g), imidazole (1.70 g), potassium carbonate (2.80 g) and N, N-dimethylformamide (15 ml). The mixture was stirred at 130 ° C. for 2.5 hours. Water was added to the reaction mixture, pH was adjusted to 6 with 2N hydrochloric acid, and the precipitated crystals were collected by filtration, and 4- (4-chlorophenyl) -2- (1-imidazolyl) -5-oxazolepropionic acid (1.35 g,
(85% yield). Recrystallized from methanol. Colorless needles. Melting point 194-195 [deg.] C.

Example 25 In the same manner as in Example 24, 4- (4-chlorophenyl) -2 was prepared by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with 2-methylimidazole. -(2-Methyl-1-imidazolyl) -5
-Oxazolepropionic acid was obtained (54% yield). Recrystallized from methanol. Colorless needles. Melting point 195-1
97 ° C. Example 26 In a manner similar to Example 24, 4- (4-chlorophenyl) -2- (2 was obtained by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with 2-ethylimidazole. -Ethyl-1-imidazolyl) -5
-Oxazolepropionic acid was obtained (88% yield). Recrystallized from methanol. Colorless needles. Melting point 197-1
99 ° C.

Example 27 In a manner similar to Example 24, 4- (4-chlorophenyl) -2 was prepared by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with 2-phenylimidazole. -(2-Phenyl-1-imidazolyl)
-5-Oxazolepropionic acid was obtained (yield 29
%). Recrystallized from ethanol. Colorless needles. Melting point 1
79-180 ° C. Example 28 In a manner similar to Example 24, 4- (4-chlorophenyl) -2 was obtained by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid with pyrazole.
-(1-Pyrazolyl) -5-oxazolepropionic acid was obtained (yield 91%). Recrystallized from methanol. Colorless needles. Melting point 171-172 [deg.] C.

Example 29 In the same manner as in Example 24, 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionic acid and 1,
By reaction with 2,4-triazole, 4- (4-chlorophenyl) -2- (1,2,4-triazole-1-
Yl) -5-oxazolepropionic acid was obtained (yield 9
1%). Recrystallized from ethanol. Colorless prism crystals.
Melting point 168-169 [deg.] C. Example 30 Methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate (1.50 g) and 2-propylimidazole (0.66 g) were dissolved in N, N-dimethylformamide (10 ml). Sodium hydride (60%, oily, 0.30 g) was gradually added to the resulting solution at room temperature. After stirring at room temperature for 3.5 hours, 2N aqueous sodium hydroxide solution (50 ml) was added, and the mixture was further stirred for 30 minutes. Add water to the reaction mixture and add 2N hydrochloric acid to pH.
The crystals precipitated after adjusting to 6 were collected by filtration and recrystallized from ethanol to give 4- (4-chlorophenyl) -2- (2-propyl-1-imidazolyl) -5-oxazolepropionic acid (1.25 g, Yield 69%) was obtained. Light brown needle crystals. Melting point 174-175 [deg.] C.

Example 31 In the same manner as in Example 30, methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate was reacted with 2-isopropylimidazole and then hydrolyzed to give 4 -(4-chlorophenyl)-
2- (2-Isopropyl-1-imidazolyl) -5-oxazolepropionic acid was obtained (yield 59%). Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 173-1
74 ° C. Example 32 In a manner similar to Example 30, 4- (4) was obtained by reacting methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate with 2-methylthioimidazole and then hydrolyzing the resulting mixture. -Chlorophenyl) -2
-(2-Methylthio-1-imidazolyl) -5-oxazolepropionic acid was obtained (yield 87%). It was recrystallized from chloroform-ethanol. Colorless needles. Melting point 22
5 to 226 ° C.

Example 33 In the same manner as in Example 30, by reacting methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate with 4,5-dimethylimidazole and then hydrolyzing the resulting mixture. , 4- (4-chlorophenyl)-
2- (4,5-Dimethyl-1-imidazolyl) -5-oxazolepropionic acid was obtained (yield 77%). It was recrystallized from chloroform-methanol. Light brown needle crystals. Melting point 225-226 [deg.] C. Example 34 In the same manner as in Example 30, 4- (4-chlorophenyl) was obtained by reacting methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate and benzimidazole and then hydrolyzing them. ) -2- (1-
Benzimidazolyl) -5-oxazolepropionic acid was obtained (yield 82%). It was recrystallized from chloroform-methanol. Light brown prismatic crystals. Melting point 217-218
° C.

Example 35 In the same manner as in Example 30, by reacting methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolepropionate with 3,5-dimethylpyrazole and then hydrolyzing the same. , 4- (4-chlorophenyl) -2
-(3,5-Dimethyl-1-pyrazolyl) -5-oxazolepropionic acid was obtained (yield 90%). Recrystallized from ethanol. Colorless needles. 201-202 ° C. Example 36 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolepropionic acid (1.
Lithium aluminum hydride (185 mg) was gradually added to a solution of 47 g) in tetrahydrofuran (20 ml) at room temperature. After stirring for 1 hour, water (2 ml) was added to the reaction mixture under ice cooling, and the mixture was further stirred for 30 minutes. Diethyl ether (50 ml) was added to the reaction mixture, and the mixture was dried (M
After gSO ₄ ) the insoluble material was filtered off. The filtrate was concentrated and the precipitated crystals were collected by filtration, and 4- (4-chlorophenyl) -2-
(2-Methyl-1-imidazolyl) -5-oxazolepropanol (435 mg, yield 31%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 128-129 [deg.] C.

Example 37 4- (4-chlorophenyl) was prepared in the same manner as in Example 36.
2- (1-Pyrazolyl) -5-oxazolepropionic acid was reduced with lithium aluminum hydride to give 4- (4-chlorophenyl) -2- (1-pyrazolyl) -5-oxazolepropanol (yield). Rate 33
%). Recrystallized from diethyl ether-hexane. Colorless prism crystals. Melting point 75-76 [deg.] C. Example 38 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazole propanol (32
To a solution of 0 mg), 1,2,4-triazole (140 mg) and tributylphosphine (410 mg) in tetrahydrofuran (10 ml), a solution of diethyl azodicarboxylate in toluene (40%, 880 mg) was added dropwise at room temperature. After stirring for 1 hour, the reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. From the elution part of acetone-hexane (2: 1, v / v), 1- [3
-[4- (4-chlorophenyl) -2- (2-methyl-
1-imidazolyl) -5-oxazolyl] propyl]-
1,2,4-triazole (305 mg, yield 82%)
I got Recrystallized from acetone-isopropyl ether. Colorless prism crystals. 142-143 ° C.

Example 39 4- (4-chlorophenyl) was prepared in the same manner as in Example 38.
2- (2-Methyl-1-imidazolyl) -5-oxazolepropanol was reacted with 2-methoxyphenol to give 4- (4-chlorophenyl) -5- [3- (2
-Methoxyphenoxy) propyl] -2- (2-methyl-1-imidazolyl) oxazole was obtained (yield 54
%). Recrystallized from diethyl ether-hexane. Colorless needles. Melting point 84-85 [deg.] C. Example 40 In the same manner as in Example 38, 4- (4-chlorophenyl)
2- [2-Methyl-1-imidazolyl) -5-oxazolepropanol was reacted with 1-methylhydantoin to give 3- [3- [4- (4-chlorophenyl) -2
-(2-Methyl-1-imidazolyl) -5-oxazolyl] propyl] -1-methylhydantoin was obtained (77% yield). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. 105-106 ° C.

Example 41 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolepropionic acid (1.
00g) and triethylamine (365mg) in tetrahydrofuran (40ml) solution, ethyl chlorocarbonate (3
95 mg) was added dropwise at -30 ° C. After stirring for 40 minutes, the reaction mixture was added to a mixed solution of aqueous ammonia (28%, 30 ml) and tetrahydrofuran (10 ml) at 0 ° C, and stirred at room temperature for 1 hour. Pour the reaction mixture into water,
The precipitated crystals were collected by filtration, and 4- (4-chlorophenyl)-
2- (2-Methyl-1-imidazolyl) -5-oxazolepropionamide (900 mg, yield 90%) was obtained. Recrystallized from methanol-ethyl acetate. Colorless needles. Melting point 215-216 [deg.] C. Example 42 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolepropionic acid (1.
50 g) and triethylamine (550 mg) in tetrahydrofuran (40 ml) was added with ethyl chlorocarbonate (5
90 mg) was added dropwise at -30 ° C. After stirring for 30 minutes, the reaction mixture was treated with 2-chloroethylamine hydrochloride (2.6
2g), triethylamine (2.29g) and N, N
-Into a solution prepared from dimethylformamide (20 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, the precipitated crystals were collected by filtration, and N- (2-chloroethyl) -4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepropionamide (1 0.53 g, yield 86%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 155
~ 156 ° C.

Example 43 In the same manner as in Example 42, 4- (4-chlorophenyl) was used.
N- (2-chloroethyl) -4- (4-chlorophenyl) -2- (1-imidazolyl) -5-oxazolepropionamide was obtained from 2- (1-imidazolyl) -5-oxazolepropionic acid (yield 77%). Recrystallized from acetone-isopropyl ether. Colorless needles. Melting point 130-131 [deg.] C. Example 44 In a similar manner to Example 42, 4- (4-chlorophenyl)
-2- (1,2,4-triazol-1-yl) -5-
Oxazolepropionic acid to N- (2-chloroethyl) -4- (4-chlorophenyl) -2- (1,2,4)
-Triazol-1-yl) -5-oxazolepropionamide was obtained (yield 87%). Recrystallized from ethyl acetate-isopropyl ether. Colorless needles. Melting point 15
7-158 ° C.

Example 45 4- (4-chlorophenyl) -2- (2-pyridylthio) -5-oxazolepropionic acid (1.20 g) and triethylamine (405 mg) in tetrahydrofuran (30 ml) was dissolved in ethyl chlorocarbonate (435 mg). )
Was added dropwise at -30 ° C. After stirring for 30 minutes, the reaction mixture was added at 0 ° C. to a solution prepared from 2-chloroethylamine hydrochloride (1.93 g), triethylamine (1.68 g) and N, N-dimethylformamide (20 ml), and stirred at room temperature for 1 hour. Stir the time. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and evaporated, the residue was subjected to silica gel column chromatography. From the acetone-hexane (1: 2, v / v) eluate, N- (2-chloroethyl) -4- (4-chlorophenyl) -2- (2-pyridylthio) -5-oxazolepropionamide (1.2
9 g, yield 91%) was obtained as an oil. NMR (δ ppm in
CDCl ₃ ): 2.65 (2H, t, J = 7.5Hz), 3.29 (2H, t, J = 7.5Hz),
3.4 ~ 3.6 (4H, m), 6.24 (1H, brs), 7.21 (1H, ddd, J = 7.5 & 5 & 1
Hz), 7.35 ~ 7.5 (3H, m), 7.6 ~ 7.75 (3H, m), 8.49 (1H, dd, J =
5 & 1Hz). Example 46 N- (2-chloroethyl) -4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepropionamide (1.30 g) was added to N, N-.
A solution obtained by dissolving in dimethylformamide (30 ml) was added with sodium hydride (60%, oily, 265 m
g) was added slowly at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated, and the precipitated crystals were collected by filtration, and 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-
[2- (2-Oxazolin-2-yl) ethyl] oxazole (1.07 g, yield 91%) was obtained. Acetone-
Recrystallized from isopropyl ether. Colorless prism crystals. 119-120 ° C.

Example 47 In the same manner as in Example 46, N- (2-chloroethyl)-
Ring closure of 4- (4-chlorophenyl) -2- (1-imidazolyl) -5-oxazolepropionamide yields 4
-(4-chlorophenyl) -2- (1-imidazolyl)
-5- [2- (2-Oxazolin-2-yl) ethyl]
Oxazole was obtained (yield 69%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. 120-121 ° C. Example 48 In the same manner as in Example 46, N- (2-chloroethyl)-
4- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -5-oxazolepropionamide is ring-closed to give 1- [4- (4-chlorophenyl)-
5- [2- (2-oxazolin-2-yl) ethyl]-
2-Oxazolyl] -1,2,4-triazole was obtained (yield 85%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. 132-133 ° C.

Example 49 In the same manner as in Example 46, N- (2-chloroethyl)-
4- (4-chlorophenyl) -2- (2-pyridylthio) -5-oxazolepropionamide was ring-closed, the reaction mixture was poured into water for extraction, washed with water and dried (MgS
O ₄₎ were later subjected residue obtained by distilling off the solvent to silica gel column chromatography. From acetone-hexane (1: 2, v / v) eluate, 4- (4-chlorophenyl) -2- (2-pyridylthio) -5- [2- (2-
Oxazolin-2-yl) ethyl] oxazole was obtained as an oil (yield 67%). NMR (δ ppm in CDCl ₃ ):
2.65 ~ 2.8 (2H, m), 3.2 ~ 3.35 (2H, m), 3.80 (2H, t, J = 9.5H
z), 4.21 (2H, t, J = 9.5Hz), 7.16 (1H, ddd, J = 7.5 & 5 & 1Hz),
7.35 ~ 7.45 (3H, m), 7.55 ~ 7.7 (3H, m), 8.4 (1H, ddd, J = 5 & 2
& 0.5Hz).

Example 50 4- (4-chlorophenyl) -2- (2-ethyl-1-)
Imidazolyl) -5-oxazolepropionic acid (1.
20 g) and triethylamine (420 mg) in tetrahydrofuran (40 ml) solution, ethyl chlorocarbonate (4
50 mg) was added dropwise at -30 ° C. After stirring for 1 hour, the reaction mixture was treated with 2-chloroethylamine hydrochloride (2.0
1 g), triethylamine (1.76 g) and tetrahydrofuran (40 ml) were added to the solution at 0 ° C., and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), and then the solvent was distilled off to precipitate crystals (91
0 mg) was collected by filtration. The crystals were added to potassium carbonate (370
mg) with N, N-dimethylformamide (20 m
Stirring in l) at 90-100 ° C for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and evaporated, the residue was subjected to silica gel column chromatography. Acetone-hexane (2: 3, v / v) eluted from 4- (4
-Chlorophenyl) -2- (2-ethyl-1-imidazolyl) -5- [2- (2-oxazolin-2-yl) ethyl] oxazole (320 mg, yield 25%) was obtained. Recrystallized from isopropyl ether. Colorless prism crystals. 53-54 ° C. Example 51 In a similar manner to Example 50, 4- (4-chlorophenyl)
2- (1-Pyrazolyl) -5-oxazolepropionic acid was reacted with 2-chloroethylamine, followed by ring closure to give 4- (4-chlorophenyl) -5- [2- (2-
Oxazolin-2-yl) ethyl] -2- (1-pyrazolyl) oxazole was obtained (yield 42%). Acetone-
Recrystallized from isopropyl ether. Colorless needles. 79-80 ° C.

Example 52 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolepropionic acid (50
0 mg), potassium carbonate (310 mg), iodoethane (350 mg) and N, N-dimethylformamide (10 ml) were stirred at room temperature for 16 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), then the solvent was distilled off,
The precipitated crystals were collected by filtration and 4- (4-chlorophenyl) -2
Ethyl-(2-methyl-1-imidazolyl) -5-oxazolepropionate (495 mg, 91%) was obtained.
Recrystallized from acetone-hexane. Colorless prism crystals.
Melting point 70-71 ° C. Example 53 In a similar manner to Example 52, 4- (4-chlorophenyl)
2- (2-methyl-1-imidazolyl) -5-oxazolepropionic acid was reacted with benzyl bromide to give 4
Benzyl-(4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepropionate was obtained (yield 88%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 71-72
° C.

Example 54 In a similar manner to Example 52, 4- (4-chlorophenyl)
Reaction of 2- (1-imidazolyl) -5-oxazolepropionic acid with iodoethane gave ethyl 4- (4-chlorophenyl) -2- (1-imidazolyl) -5-oxazolepropionate (yield 92 %). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 67-68 [deg.] C. Example 55 In a similar manner to Example 52, 4- (4-chlorophenyl)
-2- (1,2,4-triazol-1-yl) -5-
By the reaction of oxazolepropionic acid with iodoethane, 4- (4-chlorophenyl) -2- (1,2,4-
Ethyl triazol-1-yl) -5-oxazolepropionate was obtained (yield 93%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 9
9-100 ° C.

Example 56 4- (4-chlorophenyl) was prepared in the same manner as in Example 52.
2- (2-Pyridylthio) -5-oxazolepropionic acid was reacted with iodoethane, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. From the elution part of ethyl acetate-hexane (1: 4, v / v), 4-
(4-chlorophenyl) -2- (2-pyridylthio)-
Ethyl 5-oxazolepropionate was obtained as an oil (yield 96%). NMR (δ ppm in CDCl ₃ ): 1.22 (3H, t,
J = 7Hz), 2.74 (2H, t, J = 7.5Hz), 3.25 (2H, t, J = 7.5Hz), 4.
12 (2H, q, J = 7Hz), 7.16 (1H, ddd, J = 7.5 & 5 & 1Hz), 7.35 ~ 7.
45 (3H, m), 7.55-7.7 (3H, m), 8.48 (1H, ddd, J = 5 & 2 & 1Hz). Example 57 Ethyl 4- (4-chlorophenyl) -2- (1-imidazolyl) -5-oxazolepropionate (1.15
Lithium aluminum hydride (135 mg) was gradually added to a solution of g) in tetrahydrofuran (20 ml) at 0 ° C. After stirring for 2 hours, water (0.3 ml) was added to the reaction mixture under ice cooling, the insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 4- (4-chlorophenyl) -2- (1-imidazolyl) -5-oxazolepropanol (690 mg, from an acetone-hexane (1: 2, v / v) eluate).
68%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. 114-115 ° C.

Example 58 In a similar manner to Example 57, 4- (4-chlorophenyl)
-2- (1,2,4-triazol-1-yl) -5-
By reducing ethyl oxazolepropionate with lithium aluminum hydride, 4- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl)
-5-Oxazole propanol was obtained (yield 42
%). Recrystallized from methanol-isopropyl ether. Colorless prism crystals. 139-140 ° C. Example 59 In a similar manner to Example 57, 4- (4-chlorophenyl)
By reducing ethyl-2- (2-pyridylthio) -5-oxazolepropionate with lithium aluminum hydride, 4- (4-chlorophenyl) -2- (2-
Pyridylthio) -5-oxazole propanol was obtained (yield 81%). Recrystallized from diethyl ether-isopropyl ether. Colorless prism crystals. Melting point 70-71
° C.

Example 60 A mixture of 4- (4-chlorophenyl) -5- (2-cyanoethyl) -2- (2-methyl-1-imidazolyl) oxazole (350 mg), cysteamine (175 mg) and 2-propanol is refluxed. Stirred down for 24 hours. Water was added to the reaction mixture, and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried (MgSO _4), the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. Acetone-hexane (1: 1, v /
v) From the elution part, 4- (4-chlorophenyl) -2-
(2-Methyl-1-imidazolyl) -5- [2- (2-
Thiazolin-2-yl) ethyl] oxazole (320
mg, 77%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 94-95
° C. Example 61 In the same manner as in Example 1, 2-chloro- was prepared by reacting methyl 4- [4- (4-chlorophenyl) -2-oxo-4-oxazolin-5-yl] butanoate with phosphorus oxychloride. Methyl 4- (4-chlorophenyl) -5-oxazolebutanoate was obtained (yield 69%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 73-74 [deg.] C.

Example 62 In the same manner as in Example 2, 2-chloro-4- (4-chlorophenyl) was obtained by hydrolyzing methyl 2-chloro-4- (4-chlorophenyl) -5-oxazolebutanoate. -5-Oxazolebutanoic acid was obtained (yield 76
%). Recrystallized from acetone-ethyl acetate. Colorless prism crystals. 150-151 ° C. Example 63 In a manner similar to Example 24, 4- (4-chlorophenyl) -2- (2 was obtained by reacting 2-chloro-4- (4-chlorophenyl) -5-oxazolebutanoic acid with 2-methylimidazole. -Methyl-1-imidazolyl) -5-oxazolebutanoic acid was obtained (yield 76%). Recrystallized from tetrahydrofuran-methanol. Colorless prism crystals. Melting point 211-212 [deg.] C.

Example 64 4- (4-chlorophenyl) was prepared in the same manner as in Example 52.
2- (2-Methyl-1-imidazolyl) -5-oxazolebutanoic acid was reacted with iodoethane to give 4-
Ethyl (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolebutanoate was obtained (yield 88%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. 72-73 ° C. Example 65 4- (4-chlorophenyl) -2- (2-methyl-1-)
Ethyl imidazolyl) -5-oxazolebutanoate (9
Lithium aluminum hydride (110 mg) was gradually added to a solution of 60 mg) in tetrahydrofuran (20 ml) at 0 ° C. After stirring for 2 hours, water was added to the reaction mixture under ice cooling, the insoluble material was filtered off, and the filtrate was concentrated to precipitate 4- (4-chlorophenyl) -2- (2-methyl-1).
-Imidazolyl) -5-oxazole butanol (75
0 mg, 88%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 110-1
11 ° C.

Example 66 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolebutanoic acid (1.00
g) and triethylamine (350 mg) in tetrahydrofuran (20 ml) -N, N-dimethylformamide (10 ml) solution, ethyl chlorocarbonate (375 mg) was added dropwise at -30 ° C. After stirring for 30 minutes, the reaction mixture was added at 0 ° C. to a solution prepared from 2-chloroethylamine hydrochloride (1.68 g), triethylamine (1.45 g) and N, N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 1 hour. Stir the time. Pour the reaction mixture into water,
The precipitated crystals were collected by filtration and N- (2-chloroethyl) -4-
(4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolebutanamide (1.00
g, 85%). Recrystallized from ethyl acetate-hexane. Colorless needles. 131-132 ° C. Example 67 Sodium hydride (60%, oily, 130 mg) in N-
(2-chloroethyl) -4- (4-chlorophenyl)-
A solution of 2- (2-methyl-1-imidazolyl) -5-oxazolebutanamide (870 mg) in N, N-dimethylformamide (30 ml) was gradually added at room temperature. After stirring at room temperature for 4 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry (Mg
SO ₄₎ after, to filtrate the deposited crystal and evaporated to 4
There was obtained-(4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-oxazolin-2-yl) propyl] oxazole (615 mg, 78%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 88-89 [deg.] C.

Example 68 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolepropionic acid (1.
50 g) and N, O-dimethylhydroxylamine hydrochloride (490 mg) in N, N-dimethylformamide (50
(ml) solution, triethylamine (505 mg) was added dropwise at 0 ° C. 1-Hydroxybenzotriazole monohydrate (HOBt) (760 mg) and 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (WSC) (950 mg) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water, made alkaline with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated, and the precipitated crystals were collected by filtration, and N-methoxy-N-methyl-4- (4-chlorophenyl) -2- (2-methyl-). 1-Imidazolyl) -5-oxazolepropionamide (1.54
g, 91%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 116-117
° C. Example 69 N-methoxy-N-methyl-4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepropionamide (800 mg) in tetrahydrofuran (40 ml) was dissolved in diisobutyl hydride. Aluminum (DIBAL-H) toluene solution (1.0
M) (8.5 ml) was added dropwise at -70 ° C. After stirring for 3 hours, water was added to the reaction mixture, the mixture was neutralized with acetic acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. From ethyl acetate-hexane (1: 3, v / v) eluate, 4- (4
-Chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepropionaldehyde (47
5 mg, 70%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 109-1
10 ° C.

Example 70 4- (4-chlorophenyl) -2- (2-methyl-1-)
A mixture of imidazolyl) -5-oxazolepropionaldehyde (220 mg), cysteamine (65 mg), p-toluenesulfonic acid monohydrate (15 mg) and toluene (20 ml) was stirred under reflux for 1 hour. Ethyl acetate was added to the reaction mixture. Ethyl acetate was separated, washed with saturated aqueous sodium hydrogen carbonate and then with water, dried (MgSO ₄ ), and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography.
From the elution part of acetone-hexane (2: 1, v / v), 2
-[2- [4- (4-Chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolyl] ethyl] thiazolidine (230 mg, 88%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 110-111 [deg.] C. Example 71 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazole propanol (20
Methanesulfonyl chloride (215 mg) was added dropwise to a solution of 0 mg) and triethylamine (190 mg) in tetrahydrofuran (20 ml) at room temperature. After stirring for 12 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. Acetone-hexane (1: 1,
v / v) From the elution part, methanesulfonic acid 3- [4- (4
-Chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolyl] propyl (180 mg, 7
2%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 97-98 [deg.] C.

Example 72 3- [4- (4-chlorophenyl) -methanesulfonic acid-
2- (2-Methyl-1-imidazolyl) -5-oxazolyl] propyl (400 mg), imidazole (140
mg), potassium carbonate (280 mg) and N, N-dimethylformamide (20 ml) at 100-1.
Stir at 10 ° C. for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (M
After gSO ₄ ) the solvent was evaporated and the resulting residue was subjected to silica gel column chromatography. Methanol-
From the chloroform (5:95, v / v) elution part, 4-
(4-Chlorophenyl) -5- [3- (1-imidazolyl) propyl] -2- (2-methyl-1-imidazolyl) oxazole (230 mg, 62%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. 133-134 ° C. Example 73 Methanesulfonic acid 3- [4-
4- (4-chlorophenyl) -2- (2 by reaction of (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolyl] propyl with pyrazole.
-Methyl-1-imidazolyl) -5- [3- (1-pyrazolyl) propyl] oxazole was obtained (yield 54
%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 129-130 [deg.] C.

Example 74 4- (4-chlorophenyl) -in the same manner as in Example 38.
2- [2-Methyl-1-imidazolyl) -5-oxazolepropanol was reacted with 2,4-oxazolidinedione to give 3- [3- [4- (4-chlorophenyl)-
2- (2-Methyl-1-imidazolyl) -5-oxazolyl] propyl] -2,4-oxazolidinedione was obtained (yield 89%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 152-153
° C. Example 75 4- (4-chlorophenyl)-in the same manner as in Example 38.
2- [2-Methyl-1-imidazolyl) -5-oxazolepropanol was reacted with 2,4-thiazolidinedione to give 3- [3- [4- (4-chlorophenyl) -2.
-(2-Methyl-1-imidazolyl) -5-oxazolyl] propyl] -2,4-thiazolidinedione was obtained (yield 91%). Recrystallized from ethyl acetate-hexane. Colorless needles. 119-120 ° C.

Example 76 4- (4-chlorophenyl) -in the same manner as in Example 38.
2- (2-Methyl-1-imidazolyl) -5-oxazole By the reaction of propanol with hydantoin 3-
[3- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolyl] propyl] hydantoin was obtained (yield 65%). Methanol-
Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 19
7-198 ° C. Example 77 2- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolyl] -2-hydroxyethyl acetate (1.30 g) and thionyl chloride (3 m
The mixture of l) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ),
Crystals (1.25 g) obtained by distilling off the solvent were collected by filtration. The crystals (1.25 g) were dissolved in acetic acid (10 ml), zinc powder (5.0 g) was added, and the mixture was stirred at 100 to 110 ° C. for 1 hr. After filtering off the zinc powder, the filtrate is concentrated,
Saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. Ethyl acetate-hexane (2: 3, v /
v) From the elution part, 4- (4-chlorophenyl) -2-
Ethyl (2-methyl-1-imidazolyl) -5-oxazole acetate (960 mg, 77%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 133-
134 ° C.

Example 78 In the same manner as in Example 57, 4- (4-chlorophenyl)
2- (2-Methyl-1-imidazolyl) -5-oxazole-ethyl acetate is reduced with lithium aluminum hydride to give 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- Oxazole ethanol was obtained (yield 48%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 159-160
° C. Example 79 5- [4- (4-chlorophenyl) -2-oxo-4-
Ethyl oxazolin-5-yl] pentanoate (17.2
g), phosphorus oxychloride (32.6 g) and pyridine (4.20 g) were stirred at 120-130 ° C for 80 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off and the obtained residue was subjected to silica gel column chromatography. From the ethyl acetate-hexane (1: 3, v / v) eluate, 2-chloro-4- (4
Ethyl -chlorophenyl) -5-oxazolepentanoate was obtained as an oil (14.1 g, 78%). NMR (δ
ppm in CDCl ₃ ): 1.25 (3H, t, J = 7Hz), 1.6〜1.85 (4H, m),
2.34 (2H, t, J = 6.5Hz), 2.86 (2H, t, J = 7Hz), 4.13 (2H, q, J
= 7Hz), 7.39 (2H, d, J = 8.5Hz), 7.53 (2H, d, J = 8.5Hz).

Example 80 The same procedure as in Example 79 was carried out by reacting ethyl 6- [4- (4-chlorophenyl) -2-oxo-4-oxazolin-5-yl] hexanoate with phosphorus oxychloride to give 2-. Ethyl chloro-4- (4-chlorophenyl) -5-oxazolehexanoate was obtained as an oil (yield 70%).
NMR (δ ppm in CDCl ₃ ): 1.25 (3H, t, J = 7Hz), 1.3-1.85
(6H, m), 2.31 (2H, t, J = 7.5Hz), 2.85 (2H, t, J = 7.5Hz), 4.
13 (2H, q, J = 7Hz), 7.39 (2H, d, J = 8.5Hz), 7.53 (2H, d, J = 8.
5Hz). Example 81 2-Chloro-4- (4-chlorophenyl) -5-oxazole ethyl pentanoate (10.0 g), 2-methylimidazole (7.20 g), potassium carbonate (12.1 g).
g) and N, N-dimethylformamide (80 ml)
The mixture was stirred at 120-130 ° C for 2 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, and 4- (4-
Ethyl chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepentanoate (9.97)
g, 88%) was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 93-94
° C.

Example 82 2-Chloro-4- (4-chlorophenyl) -5-oxazole Ethyl hexanoate (3.53 g), 2-Methylimidazole (2.44 g), potassium carbonate (4.10)
g) and N, N-dimethylformamide (50 ml)
The mixture was stirred at 120-125 ° C for 3 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. From ethyl acetate-hexane (1: 1, v / v) eluate, ethyl 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolehexanoate was obtained as an oil (3.48 g). , 87%). NM
R (δ ppm in CDCl ₃ ): 1.25 (3H, t, J = 7Hz), 1.35 ~ 1.9 (6
H, m), 2.31 (2H, t, J = 7.5Hz), 2.77 (3H, s), 2.91 (2H, t, J =
7.5Hz), 4.12 (2H, q, J = 7Hz), 7.01 (1H, d, J = 1.5Hz), 7.42
(2H, d, J = 8.5Hz), 7.48 (1H, d, J = 1.5Hz), 7.60 (2H, d, J = 8.
5Hz). Example 83 4- (4-chlorophenyl) -2- (2-methyl-1-)
Lithium aluminum hydride (615 mg) was gradually added to a solution of ethyl imidazolyl-5-oxazolepentanoate (6.00 g) in tetrahydrofuran (80 ml) at 0 ° C. After stirring for 2 hours, water (1 ml) was added to the reaction mixture under ice cooling, the insoluble material was filtered off, and the filtrate was concentrated to precipitate 4- (4-chlorophenyl) -2-.
(2-Methyl-1-imidazolyl) -5-oxazolepentanol (4.20 g, 79%) was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 94-95
° C.

Example 84 4- (4-chlorophenyl) -2- (2-methyl-1-)
Lithium aluminum hydride (340 mg) was gradually added to a solution of imidazolyl) -5-oxazoleethylhexanoate (3.40 g) in tetrahydrofuran (40 ml) at 0 ° C. After stirring for 1 hour, water (1 ml) was added to the reaction mixture under ice cooling, the insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazole was eluted from the acetone-hexane (1: 1, v / v) eluate. Hexanol (2.74 g, 90%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 7
0-71 ° C. Example 85 4- (4-chlorophenyl) was prepared in the same manner as in Example 71.
2- (2-Methyl-1-imidazolyl) -5-oxazolebutanol and methanesulfonyl chloride give 4- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) methanesulfonate. ) -5-Oxazolyl] butyl was obtained (yield 85%). Acetone-
Recrystallized from diethyl ether. Colorless prism crystals. 100-101 ° C.

Example 86 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazole pentanol (2.
Methanesulfonyl chloride (1.43 g) was added dropwise to a solution of 16 g) and triethylamine (1.26 g) in tetrahydrofuran (40 ml) at room temperature. After stirring for 2 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), the residue obtained by evaporating the solvent was subjected to silica gel column chromatography. Acetone-hexane (1: 1, v / v)
From the elution part, 5- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -methanesulfonic acid-
5-oxazolyl] pentyl was oily (2.47 g, 9
3%). NMR (δ ppm in CDCl ₃ ): 1.45 to 1.9
(6H, m), 2.78 (3H, s), 2.94 (2H, t, J = 7.5Hz), 3.00 (3H,
s), 4.24 (2H, t, J = 6Hz), 7.01 (1H, d, J = 1.5Hz), 7.43 (2H,
d, J = 8.5Hz), 7.48 (1H, d, J = 1.5Hz), 7.60 (2H, d, J = 8.5H
z). Example 87 In the same manner as in Example 86, 4- (4-chlorophenyl)
2- (2-Methyl-1-imidazolyl) -5-oxazolehexanol was reacted with methanesulfonyl chloride to give 6- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) methanesulfonate. ) -5-Oxazolyl] hexyl was obtained as an oil (yield 93
%). NMR (δ ppm in CDCl ₃ ): 1.4 to 1.9 (8H, m), 2.78 (3
H, s), 2.92 (2H, t, J = 7.5Hz), 3.00 (3H, s), 4.23 (2H, t, J =
6.5Hz), 7.01 (1H, d, J = 1.5Hz), 7.43 (2H, d, J = 8.5Hz), 7.
48 (1H, d, J = 1.5Hz), 7.61 (2H, d, J = 8.5Hz).

Example 88 4- (4-chlorophenyl) -2- (2-methyl-1-)
Imidazolyl) -5-oxazolebutanol (330
mg), 1,2,4-triazole (105 mg) and tributylphosphine (300 mg) in tetrahydrofuran (10 ml), diethyl azodicarboxylate (260 mg) was added dropwise under ice water. After stirring at room temperature for 1 hour, the reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. From the elution part of methanol-chloroform (5:95, v / v), 1- [4-
[4- (4-chlorophenyl) -2- (2-methyl-1
-Imidazolyl) -5-oxazolyl] butyl] -1,
2,4-triazole (205 mg, 54%) was obtained.
Recrystallized from ethyl acetate-diethyl ether. Colorless prism crystals. Melting point 74-75 [deg.] C. Example 89 Methanesulfonic acid 4- [4- (4-chlorophenyl)-
2- (2-Methyl-1-imidazolyl) -5-oxazolyl] butyl (600 mg), imidazole (200 m
g), potassium carbonate (405 mg) and N, N-dimethylformamide (10 ml) at 100-11.
Stir for 90 minutes at 0 ° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (M
MgSO ₄₎ after the residue was subjected obtained by evaporating the solvent to silica gel column chromatography. Methanol-
From the chloroform (3:97, v / v) elution part, 4-
(4-chlorophenyl) -5- [4- (1-imidazolyl) butyl] -2- (2-methyl-1-imidazolyl)
Oxazole (310 mg, 55%) was obtained. Recrystallized from ethyl acetate-diethyl ether. Colorless prism crystals. Melting point 84-85 [deg.] C.

Example 90 Methanesulfonic acid 5- [4- (4-chlorophenyl)-
2- (2-Methyl-1-imidazolyl) -5-oxazolyl] pentyl (2.20 g), imidazole (710
mg), potassium carbonate (1.43 g) and N, N-dimethylformamide (40 ml) at 80-90.
Stir at ℃ for 3 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (MgS
O ₄₎ were later subjected residue obtained by distilling off the solvent to silica gel column chromatography. From the methanol-chloroform (3:97, v / v) elution part, 4- (4-
Chlorophenyl) -5- [5- (1-imidazolyl) pentyl] -2- (2-methyl-1-imidazolyl) oxazole (1.45 g, 71%) was obtained. This oil (1.45 g) was dissolved in methanol (6 ml), and 4N hydrochloric acid-ethyl acetate solution (2 ml) was added. Ethyl acetate was added to the reaction mixture, and the precipitated white powder was collected by filtration, washed with ethyl acetate and acetone, and then 4- (4-chlorophenyl) -5- [5- (1-imidazolyl) pentyl] -2.
-(2-Methyl-1-imidazolyl) oxazole dihydrochloride monohydrate (1.47 g, 58%) was obtained. Melting point 19
7-199 ° C. Example 91 6- [4- (4-chlorophenyl) -methanesulfonate
2- (2-Methyl-1-imidazolyl) -5-oxazolyl] hexyl (2.11 g), imidazole (660
mg), potassium carbonate (1.33 g) and N, N-dimethylformamide (40 ml) at 90-95.
Stirred at ° C for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (MgS
O ₄₎ were later subjected residue obtained by distilling off the solvent to silica gel column chromatography. From the methanol-chloroform (3:97, v / v) elution part, 4- (4-
Chlorophenyl) -5- [6- (1-imidazolyl) hexyl] -2- (2-methyl-1-imidazolyl) oxazole (1.26 g, 64%) was obtained. This oil (1.26 g) was dissolved in methanol (5 ml), and 4N hydrochloric acid-ethyl acetate solution (1.7 ml) was added. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the precipitated white powder was collected by filtration. Recrystallization from methanol-acetone to give 4- (4-chlorophenyl) -5- [6- (1-imidazolyl) hexyl] -2- (2-methyl-1-imidazolyl) oxazole dihydrochloride hemihydrate. (1.1
6 g, 49%) was obtained. Melting point 171-173C. Example 92 4- [4- (4-chlorophenyl) -methanesulfonic acid
2- (2-Methyl-1-imidazolyl) -5-oxazolyl] butyl (600 mg), ethyl 2-imidazolecarboxylate (410 mg), potassium carbonate (405 m
g) and N, N-dimethylformamide (30 ml)
The mixture was stirred at 80-90 ° C for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography. From the elution part of acetone-hexane (1: 1, v / v), 1- [4- [4- (4-chlorophenyl) -2-
Crystals of ethyl (2-methyl-1-imidazolyl) -5-oxazolyl] butyl] -2-imidazolecarboxylate (460 mg, 69%) were obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 1
34-135 ° C.

Formulation Example 1 (Production of tablets) (1) 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepropanol (compound produced in Example 36) 30 g (2 ) Lactose 50 g (3) Corn starch 15 g (4) Carboxymethyl cellulose 44 g (5) Magnesium stearate 1 g 1000 tablets 140 g (1), (2), (3) The total amount and 30 g of (4) are kneaded with water. After vacuum drying, granulation is performed. 1 at the end of this granulation
By mixing 4 g of (4) and 1 g of (5) and tableting with a tableting machine, 1000 tablets containing (1) 30 mg per tablet are produced.

Formulation Example 2 (Production of Tablet) (1) 4- (4-chlorophenyl) -5- [2- (2-oxazolin-2-yl) ethyl] -2- (1-pyrazolyl) oxazole (Example) Compound produced in 51) 100 g (2) Lactose 200 g (3) Corn starch 55 g (4) Carboxymethyl cellulose 44 g (5) Magnesium stearate 1 g 1000 tablets 400 g (1), (2), (3) total amount and 30 g (4) is kneaded with water, vacuum dried, and then granulated. 1 at the end of this granulation
By mixing 4 g of (4) and 1 g of (5) and tableting with a tableting machine, 1000 tablets containing 100 mg of (1) per tablet are produced.

[0121]

The compound (I) of the present invention or a salt thereof is
It has excellent blood glucose lowering action and insulin secretagogue action, and has low toxicity. In addition, the compound (I) of the present invention or a salt thereof can be used as an insulin secretagogue, a preventive / therapeutic agent for diabetes, an anti-arteriosclerotic agent, an antihyperlipidemic agent, an antihypertensive agent and diabetic complications (eg, nephropathy, retina It is useful as a prophylactic / therapeutic agent for diseases, neurological disorders, etc.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/44 ADN A61K 31/44 ADN 31/445 AAA 31/445 AAA 31/535 ABL 31/535 ABL 31/55 ACV 31/55 ACV C07D 263/32 C07D 263/32 263/46 263/46 263/48 263/48 271/04 271/04 271/06 271/06 271/10 271/10 413/04 211 413/04 211 231 231 233 233 235 235 235 413/12 213 413/12 213 249 249 413/14 233 413/14 233 417/12 263 417/12 263

Claims (48)

[Claims] 1. A general formula: [In the formula, R ¹ represents a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, and A is B may be substituted with an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified or amidated carboxy group. An aromatic group and Y represents a divalent aliphatic hydrocarbon group] or a salt thereof. 2. The compound according to claim 1, wherein R ¹ is an optionally substituted heterocyclic group. 3. A 5- or 6-membered ring in which the heterocyclic group contains (i) 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom other than carbon as ring-constituting atoms, or (i)
i) This 5- or 6-membered ring and a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or 5 containing 1 nitrogen atom
The compound according to claim 2, which is a condensed ring with a member ring. 4. The compound according to claim 2, wherein the heterocyclic group is an azolyl group. 5. The compound according to claim 1, wherein A is an optionally substituted heterocyclic group. 6. A 5- or 6-membered ring in which the heterocyclic group contains (i) 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon as a ring-constituting atom, or (i
i) This 5- or 6-membered ring and a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or 5 containing 1 nitrogen atom
The compound according to claim 5, which is a condensed ring with a member ring. 7. The compound according to claim 5, wherein the heterocyclic group is an azolyl group, an azolinyl group or an azolidinyl group. 8. The optionally substituted heterocyclic group represented by R ¹ and A is an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group. Ring group,
Halogen atom, nitro group, optionally substituted amino group, optionally substituted acyl group, optionally substituted hydroxy group, optionally substituted thiol group and esterified or amidated 2-pyridyl, 3-pyridyl, 4-pyridyl, which may have 1 to 3 substituents selected from the carboxy group
2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- Pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4
-Oxadiazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,
1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, benzimidazol-1-yl, benzimidazol-2-yl, Indole-1-yl, indol-3-yl, 1H-indazol-1-yl,
1H-pyrrolo [2,3-b] pyrazin-1-yl, 1H
-Pyrrolo [2,3-b] pyridin-1-yl, 1H-imidazo [4,5-b] pyridin-1-yl, 1H-imidazo [4,5-c] pyridin-1-yl, 1H-imidazo [4,5-b] pyrazin-1-yl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3- Yl, imidazolin-1-yl, imidazolin-2-yl, oxazolin-2-yl, thiazolin-2-yl,
Oxazin-2-yl, 2-oxoimidazolidine-1
-Yl, 2,4-dioxoimidazolidin-3-yl,
2,4-dioxooxazolidin-3-yl or 2,4
The compound according to claim 2 or 5, which is a -dioxothiazolidin-3-yl group. 9. The compound according to claim 1, wherein A is an optionally substituted hydroxy group. 10. R ¹ is (1) halogen atom, (2) pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2 , 4-Triazolyl, 1,2,3-triazolyl, tetrazolyl, benzimidazolyl, indolyl, 1H-indazolyl, 1H
-Pyrrolo [2,3-b] pyrazinyl, 1H-pyrrolo [2,
3-b] pyridinyl, 1H-imidazo [4,5-b] pyridinyl, 1H-imidazo [4,5-c] pyridinyl,
1H-imidazo [4,5-b] pyrazinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl or oxazinyl groups, each of which is (i)
C _1-10 alkyl group, C _2-10 alkenyl group or C _2-10 alkynyl group, (ii) C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group or C _4-10 cycloalkadienyl group, (Iii) C _6-14 aryl group, (iv) furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl , Purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenatoridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,
5-a] pyridyl, imidazo [1,2-a] pyridyl,
Imidazo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl group, (v) Oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholino or thiomorpholino group ((ii),
(Iii), (iv) and (v) are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, thienyl, furyl, pyridyl, Oxazolyl, thiazolyl, tetrahydrofuryl,
Morpholino, piperidino, pyrrolidino, piperazino, C
_7-9 aralkyl, amino, N-mono-C _1-4 alkylamino, N, N-di-C _1-4 alkylamino, C _2-8 acylamino, amidino, C _2-8 acyl, carbamoyl, N-mono -C _1-4 alkyl-carbamoyl, N, N-di-C _1-4
Alkyl-carbamoyl, sulfamoyl, N-mono-
C _1-4 alkylsulfamoyl, N, N-di-C _1-4 alkylsulfamoyl, carboxy, C _1-7 alkoxy-
Carbonyl, hydroxy, C _1-4 alkoxy, C _2-5 alkenyloxy, C _3-7 cycloalkyloxy, C _7-9 aralkyloxy, C _6-14 aryloxy, mercapto, C
_1-4 alkylthio, C _7-9 aralkylthio, C _6-14 arylthio, sulfo, cyano, azido, nitro, nitroso and halogen may have 1 to 3 substituents), (vi ) Halogen atom, (vii) nitro group, (viii) C _1-10 alkyl, C _2-10 alkenyl, C
_An amino group optionally having 1 or 2 substituents selected from _3-10 cycloalkyl, C _1-10 acyl and C _6-12 aryl, (ix) C _1-3 alkyl, C _1-3 Alkoxy,
C _1-13 acyl group optionally substituted by halogen, nitro, hydroxy or amino, (x) hydroxy group, C
_1-10 alkoxy group, C _2-10 alkenyloxy group, C _7-10
Aralkyloxy group, C _2-13 acyloxy group, C _6-14 aryloxy group which may be substituted with 1 or 2 halogens or C _1-4 alkoxy, C _1-10 alkylsulfonyloxy group, or C _{1 -6} alkyl optionally substituted C _6-12 arylsulfonyloxy group, (xi) furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- Triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1
H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl , Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b. ] Pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,
2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl substituted Optionally substituted thiol or C _1-10 alkylthio group, C optionally substituted by C _1-6 alkyl
_6-14 arylthio group, C _7-10 aralkylthio group or C
_2-13 acylthio group, (xii) carboxy group, C _1-4 alkoxy-carbonyl group, C _7-9 aralkyloxy-carbonyl group, C _6-14 aryloxy-carbonyl group or furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl , Thiazolyl, isothiazolyl, imidazolyl,
Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- Triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1
H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl , Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b. ] Pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,
2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl substituted Optionally a C _1-4 alkoxy-carbonyl group, (xiii) formula: —CON (R ⁵ ) (R ⁶ ), wherein R ⁵ and R ⁶ are each a hydrogen atom; C _1-10 alkyl, C _{2 -Ten}
Alkenyl or C _2-10 alkynyl; C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _4-10 cycloalkadienyl, furyl, thienyl, pyrrolyl, oxazolyl,
Isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl , Carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indoridinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1]. , 5-a] Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2 , 4- Triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl (these groups are C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrahydrofuryl, morpholino, piperidino, pyrrolidino, piperazino, C _7-9 aralkyl, amino, N-mono-C _1-4 alkyl Amino, N, N-di-C _1-4 alkylamino, C _2-8 acylamino, amidino, C _2-8 acyl, carbamoyl,
N-mono-C _1-4 alkyl-carbamoyl, N, N-di-C _1-4 alkyl-carbamoyl, sulfamoyl, N
-Mono-C _1-4 alkylsulfamoyl, N, N-di-
C _1-4 alkylsulfamoyl, carboxy, C _1-7 alkoxy-carbonyl, hydroxy, C _1-4 alkoxy,
C _2-5 alkenyloxy, C _3-7 cycloalkyloxy,
C _7-9 aralkyloxy, C _6-14 aryloxy, mercapto, C _1-4 alkylthio, C _7-9 aralkylthio, C
_6-14 arylthio, sulfo, cyano, azido, nitro,
Optionally substituted with 1 to 3 substituents selected from nitroso and halogen), hydroxy, C _1-10 alkoxy, C _2-10 alkenyloxy, C _7-10 aralkyloxy, C _2-13 acyloxy, C _6-14 optionally substituted by 1 or 2 halogens or C _1-4 alkoxy
A group represented by aryloxy or C _1-10 alkylsulfonyloxy] and optionally 1 to 3 substituents selected from (xiv) oxo, (3) hydroxy group, C _{1- 10} alkoxy group, C _2-10 alkenyloxy group, C _7-10 aralkyloxy group, C _2-13 acyloxy group, C _6-14 which may be substituted with 1 or 2 halogens or C _1-4 alkoxy Aryloxy group, C _1-10 alkylsulfonyloxy group or C _6-12 arylsulfonyloxy group optionally substituted with C _1-6 alkyl, (4) furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl , Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl , Carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiynyl, thianthrenyl, phenatridinyl, phenatrollinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1]. , 5-a] Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2 , 4- Triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl-substituted thiol or C _1-10 alkylthio group, C _1-6 alkyl substituted _Optionally C _6-14 arylthio group, C _7-10 aralkylthio group or C _2-13 acylthio group or (5) C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, C _1- The compound according to claim 1, which is an amino group optionally having 1 or 2 substituents selected from ₁₀ acyl and C _6-12 aryl. 11. A is (1) formyl group, C _1-10 alkyl-carbonyl group, C _3-10 cycloalkyl-carbonyl group, C _3-10 alkenyl-carbonyl group, C _3-10 cycloalkenyl-carbonyl group. Or a C _6-12 aryl-carbonyl group (these groups may be substituted with 1 to 3 C _1-3 alkyl, C _1-3 alkoxy, halogen, nitro, hydroxy or amino), (2 ) Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, benz Imidazolyl, indolyl, 1H-indazolyl, 1H
-Pyrrolo [2,3-b] pyrazinyl, 1H-pyrrolo [2,
3-b] pyridinyl, 1H-imidazo [4,5-b] pyridinyl, 1H-imidazo [4,5-c] pyridinyl,
1H-imidazo [4,5-b] pyrazinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl or oxazinyl groups, each of which is (i)
C _1-10 alkyl group, C _2-10 alkenyl group or C _2-10 alkynyl group, (ii) C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group or C _4-10 cycloalkadienyl group, (Iii) C _6-14 aryl group, (iv) furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl , Purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenatoridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,
5-a] pyridyl, imidazo [1,2-a] pyridyl,
Imidazo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl group, (v) Oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholino or thiomorpholino group ((ii),
(Iii), (iv) and (v) are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, thienyl, furyl, pyridyl, Oxazolyl, thiazolyl, tetrahydrofuryl,
Morpholino, piperidino, pyrrolidino, piperazino, C
_7-9 aralkyl, amino, N-mono-C _1-4 alkylamino, N, N-di-C _1-4 alkylamino, C _2-8 acylamino, amidino, C _2-8 acyl, carbamoyl, N-mono -C _1-4 alkyl-carbamoyl, N, N-di-C _1-4
Alkyl-carbamoyl, sulfamoyl, N-mono-
C _1-4 alkylsulfamoyl, N, N-di-C _1-4 alkylsulfamoyl, carboxy, C _1-7 alkoxy-
Carbonyl, hydroxy, C _1-4 alkoxy, C _2-5 alkenyloxy, C _3-7 cycloalkyloxy, C _7-9 aralkyloxy, C _6-14 aryloxy, mercapto, C
_1-4 alkylthio, C _7-9 aralkylthio, C _6-14 arylthio, sulfo, cyano, azido, nitro, nitroso and halogen may have 1 to 3 substituents), (vi ) Halogen atom, (vii) nitro group, (viii) C _1-10 alkyl, C _2-10 alkenyl, C
_An amino group optionally having 1 or 2 substituents selected from _3-10 cycloalkyl, C _1-10 acyl and C _6-12 aryl, (ix) C _1-3 alkyl, C _1-3 Alkoxy,
C _1-13 acyl group optionally substituted by halogen, nitro, hydroxy or amino, (x) hydroxy group, C
_1-10 alkoxy group, C _2-10 alkenyloxy group, C _7-10
Aralkyloxy group, C _2-13 acyloxy group, C _6-14 aryloxy group optionally substituted by 1 or 2 halogens or C _1-4 alkoxy, C _1-10 alkylsulfonyloxy group or C _1- C _6-12 arylsulfonyloxy group optionally substituted with ₆ alkyl, (xi) furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2 , 4-Oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2 , 4-Triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, a Benzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H
-Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl,
Quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α
-Carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indoridinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] ] Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2]
-B] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl substituted Optionally thiol or C _1-10 alkylthio group, C _6-14 optionally substituted by C _1-6 alkyl
Arylthio group, C _7-10 aralkylthio group or C _2-13
Acylthio group, (xii) carboxy group, C _1-4 alkoxy-carbonyl group, C _7-9 aralkyloxy-carbonyl group, C _6-14 aryloxy-carbonyl group or furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1, 3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl 1H
-Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl,
Quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α
-Carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indoridinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] ] Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2]
-B] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl substituted Optionally a C _1-4 alkoxy-carbonyl group, (xiii) formula: —CON (R ⁵ ) (R ⁶ ), wherein R ⁵ and R ⁶ are each a hydrogen atom; C _1-10 alkyl, C _{2 — 10} alkenyl or C _2-10 alkynyl; C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _4-10 cycloalkadienyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl , Carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiynyl, thianthrenyl, phenatridinyl, phenatrollinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1]. , 5-a] Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2 , 4- Triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl (these groups are C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrahydrofuryl, morpholino, piperidino, pyrrolidino, piperazino, C _7-9 aralkyl, amino, N-mono-C _1-4 alkyl Amino, N, N-di-C _1-4 alkylamino, C _2-8 acylamino, amidino, C _2-8 acyl, carbamoyl,
N-mono-C _1-4 alkyl-carbamoyl, N, N-di-C _1-4 alkyl-carbamoyl, sulfamoyl, N
-Mono-C _1-4 alkylsulfamoyl, N, N-di-
C _1-4 alkylsulfamoyl, carboxy, C _1-7 alkoxy-carbonyl, hydroxy, C _1-4 alkoxy,
C _2-5 alkenyloxy, C _3-7 cycloalkyloxy,
C _7-9 aralkyloxy, C _6-14 aryloxy, mercapto, C _1-4 alkylthio, C _7-9 aralkylthio, C
_6-14 arylthio, sulfo, cyano, azido, nitro,
Optionally having 1 to 3 substituents selected from nitroso and halogen); or hydroxy, C _1-10
Alkoxy, C _2-10 alkenyloxy, C _7-10 aralkyloxy, C _2-13 acyloxy, 1 or 2 halogens or C optionally substituted by C _1-4 alkoxy
_6-14 aryloxy, or C _1-10 alkylsulfonyloxy] and optionally having 1 to 3 substituents selected from (xiv) oxo, (3) hydroxy group , C _1-10 alkoxy group, C _2-10 alkenyloxy group, C _7-10 aralkyloxy group, C _2-13 acyloxy group, optionally substituted with 1 or 2 halogens or C _1-4 alkoxy C _6-14 aryloxy group, C _1-10 alkylsulfonyloxy group or C _6-12 arylsulfonyloxy group optionally substituted by C _1-6 alkyl, (4) carboxy group, C _1-4 alkoxy- Carbonyl group, C _7-9 aralkyloxy-carbonyl group, C _6-14 aryloxy-carbonyl group, or furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl , Purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenatoridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,
5-a] pyridyl, imidazo [1,2-a] pyridyl,
Imidazo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4,3-b] pyridazinyl substituted Or a C _1-4 alkoxy-carbonyl group, or (5) formula: —CON (R ⁵ ) (R ⁶ ) [wherein R ⁵ and R ⁶ are each a hydrogen atom; C _1-10 alkyl, C _{2 − 10} alkenyl or C _2-10 alkynyl; C _3-10 cycloalkyl, C
_3-10 cycloalkenyl, C _4-10 cycloalkadienyl,
Furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxalinyl. , Thianthrenyl, phenatridinyl, phenatorolinyl, indoridinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a]
Pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1, 2,4-triazolo [4,3-b] pyridazinyl (these groups are C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, Thienyl, furyl, pyridyl, oxazolyl,
Thiazolyl, tetrahydrofuryl, morpholino, piperidino, pyrrolidino, piperazino, C _7-9 aralkyl, amino, N-mono-C _1-4 alkylamino, N, N-di-
C _1-4 alkylamino, C _2-8 acylamino, amidino,
C _2-8 acyl, carbamoyl, N-mono-C _1-4 alkyl-carbamoyl, N, N-di-C _1-4 alkyl-carbamoyl, sulfamoyl, N-mono-C _1-4 alkylsulfamoyl, N , N-di-C _1-4 alkylsulfamoyl, carboxy, C _1-7 alkoxy-carbonyl, hydroxy, C _1-4 alkoxy, C _2-5 alkenyloxy,
C _3-7 cycloalkyloxy, C _7-9 aralkyloxy,
1 to 3 substituents selected from C _6-14 aryloxy, mercapto, C _1-4 alkylthio, C _7-9 aralkylthio, C _6-14 arylthio, sulfo, cyano, azido, nitro, nitroso and halogen. Or optionally hydroxy); or hydroxy, C _1-10 alkoxy, C _2-10 alkenyloxy, C _7-10 aralkyloxy, C _2-13 acyloxy, 1 or 2 halogens or C _1-4 alkoxy. The compound according to claim 1, which is a group represented by optionally substituted C _6-14 aryloxy or C _1-10 alkylsulfonyloxy]. 12. B is halogen, nitro, cyano, 1 to 3 halogens, hydroxy or C _1-6 alkoxy optionally substituted by C _1-6 alkoxy, 1 to 3 halogens, hydroxy or C. _C1-6 alkoxy optionally substituted by C _1-6 alkyl, and one to three halogen, to 1 selected from hydroxy or C _1-6 optionally C _3-7 cycloalkyl optionally substituted with alkoxy C _{6-14 optionally} having 3 substituents
Aryl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl , Benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phena. Nyl, phenoxathiynyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5] -A] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl or 1,2,4-triazolo [4] The compound according to claim 1, which is a 3,3-b] pyridazinyl group, or a salt thereof. 13. The compound according to claim 1, wherein Y is a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms. 14. The compound according to claim 1, wherein Y is a divalent aliphatic hydrocarbon group having 2 to 4 carbon atoms. 15. R ¹ is (i) halogen atom, (ii) C _1-10
Imidazolyl, pyrazolyl, 1,2,4-triazolyl optionally having 1 to 3 substituents selected from alkyl, C _6-14 aryl and C _1-10 alkylthio,
1,2,3-triazolyl, benzimidazolyl, pyrrolidinyl, piperidinyl, morpholinyl or hexamethyleneiminyl group, (iii) C _1-10 alkoxy group, (i
v) C _6-14 aryloxy group, (v) C _1-10 alkylthio group, (vi) C optionally substituted by C _1-6 alkyl
_6-14 arylthio group, (vii) C _1-6 alkyl or C
_6-14 imidazolyl optionally substituted with aryl,
1,2,3-triazolyl, 1,2,4-triazolyl or pyridyl-substituted thiol group, (viii) pyridyl-C _1-4 alkylthio group, or (ix) 1 or 2
C _1-10 alkyl or C _3-10 cycloalkyl optionally substituted amino group; A is (i) formyl group, (i
i) imidazolyl optionally substituted with C _1-10 alkyl, pyrazolyl, 1,2,4-triazolyl, 1,2,
3-triazolyl, thiazolidinyl, oxazolinyl,
Thiazolinyl, 2,4-dioxoimidazolidinyl,
2,4-dioxooxazolidinyl or 2,4-dioxothiazolidinyl group, (iii) hydroxy group, (iv)
C _6-14 aryloxy group optionally substituted by C _1-4 alkoxy, (v) C _1-10 alkylsulfonyloxy group, (vi) C _1-4 alkoxy-carbonyl group, (vii) C
_7-9 aralkyloxy-carbonyl group, or (viii)
^{Formula: -CON (R 5) (R} 6) wherein, R ⁵ and R ⁶ are each a hydrogen atom, or a C _1-10 an alkoxy or optionally C _1-10 alkyl optionally substituted with halogen] with a group represented by; B is a phenyl group optionally substituted by halogen; and Y is _{- (CH 2) 2 -,} - (CH 2) 3 -, -
_{(CH 2) 4 -, -} (CH 2) 5 - or - (CH _{2) 6} - and is a compound according to claim 1. 16. A heterocyclic group in which R ¹ is optionally substituted;
The compound according to claim 1, wherein A is a heterocyclic group which may be substituted; and Y is a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms. 17. The compound according to claim 16, wherein the heterocyclic group represented by R ¹ and A is an azolyl group, an azolinyl group or an azolidinyl group, respectively. 18. The heterocyclic group represented by R ¹ is an azolyl group,
The compound according to claim 16, wherein the heterocyclic group represented by and A is an azolyl group, an azolinyl group or an azolidinyl group. 19. The azolyl group, azolinyl group and azolidinyl group represented by R ¹ and A are pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4. A compound according to claim 16 which is a -triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl or thiazolinyl group. 20. The method of claim R ¹ is C _1-10 alkyl, C _6-14 aryl and C _1-10 1 to 3 substituents substituted azolyl group selected from alkylthio 16
A compound as described. 21. The compound according to claim 20, wherein the azolyl group is an imidazolyl, pyrazolyl, 1,2,4-triazolyl or 1,2,3-triazolyl group. 22. The compound according to claim 12, wherein A is an azolyl, azolinyl or azolidinyl group optionally substituted by 1 or 2 C _1-10 alkyl or oxo groups. 23. A is imidazolyl optionally substituted with C _1-10 alkyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolidinyl, oxazolinyl, thiazolinyl, 2,4-di The compound according to claim 16, which is an oxoimidazolidinyl, 2,4-dioxooxazolidinyl or 2,4-dioxothiazolidinyl group. 24. The compound according to claim 16, wherein B is an optionally substituted phenyl group. 25. The compound according to claim 16, wherein B is a phenyl group which may be substituted with halogen. 26. The compound according to claim 16, wherein Y is a divalent aliphatic hydrocarbon group having 3 to 5 carbon atoms. 27. The compound according to claim 16, wherein Y is — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ — or — (CH ₂ ) ₅ —. 28. A heterocyclic group in which R ¹ is optionally substituted;
The compound according to claim 1, wherein A is a hydroxy group which may be substituted; and Y is a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms. 29. The compound according to claim 28, wherein the heterocyclic group represented by R ¹ is an azolyl group. 30. An azolyl group is pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
30. The compound according to claim 29, which is a thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl group. 31. Claim R ¹ is C _1-10 alkyl, C _6-14 aryl and C _1-10 1 to 3 substituents substituted azolyl group selected from alkylthio 28
A compound as described. 32. The compound according to claim 31, wherein the azolyl group is an imidazolyl, pyrazolyl, 1,2,4-triazolyl or 1,2,3-triazolyl group. 33. A is (i) a hydroxy group, (ii) C _1-10
Alkoxy group, (iii) C _2-10 alkenyloxy group, (i
v) a C _7-10 aralkyloxy group, (v) a C _2-13 acyloxy group, (vi) a C _6-14 aryloxy group optionally substituted with 1 or 2 halogens or C _1-4 alkoxy, 29. The compound according to claim 28, which is (vii) a C _1-10 alkylsulfonyloxy group. 34. The compound according to claim 28, wherein A is a hydroxy group. 35. The compound according to claim 28, wherein B is an optionally substituted phenyl group. 36. The compound according to claim 28, wherein B is a phenyl group which may be substituted with halogen. 37. The compound according to claim 28, wherein Y is a divalent aliphatic hydrocarbon group having 3 to 5 carbon atoms. 38. The compound according to claim 28, wherein Y is — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ — or — (CH ₂ ) ₅ —. 39. 4- (4-chlorophenyl) -2- (2
The compound according to claim 1, which is -methyl-1-imidazolyl) -5-oxazole propanol or a salt thereof. 40. 4- (4-chlorophenyl) -2- (2
-Methyl-1-imidazolyl) -5-oxazolebutanol or a salt thereof. 41. 4- (4-chlorophenyl) -5- [3
The compound according to claim 1, which is-(1-imidazolyl) propyl] -2- (2-methyl-1-imidazolyl) oxazole or a salt thereof. 42. 4- (4-chlorophenyl) -2- (2
A compound according to claim 1, which is -methyl-1-imidazolyl) -5-oxazolepentanol or a salt thereof. 43. 4- (4-chlorophenyl) -5- [4
-(1-Imidazolyl) butyl] -2- (2-methyl-
The compound according to claim 1, which is 1-imidazolyl) oxazole or a salt thereof. 44. A general formula: [The symbols in the formula are as defined in claim 1. ] The compound represented by the following or a salt thereof is reacted with a halogenating agent, a general formula: [In the formula, R ^1a is a halogen atom, and other symbols are defined as in claim 1]
The meaning is as described. ] Or a salt thereof. 45. A general formula: [In the formula, R ^1a is a halogen atom, and other symbols are defined as in claim 1]
The meaning is as described. ] The compound or its salt represented by the following general formula: [In the formula, R ^1b represents an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group. ] The compound represented by the formula or a salt thereof is reacted with a general formula: [R ^1b is an optionally substituted heterocyclic group, an optionally substituted terrible group, an optionally substituted thiol group or an optionally substituted amino group, and other symbols are as defined in Claim 1 It has the same meaning as described. ] Or a salt thereof. 46. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 47. An insulin secretagogue.
The pharmaceutical composition according to any one of the preceding claims. 48. The pharmaceutical composition according to claim 46, which is a therapeutic agent for diabetes.